JP2012533578A - 17-Hydroxy-17-pentafluoroethylestradi-4,9- (10) -dien-11-aryl derivatives, preparation methods thereof, treatment of various diseases using the derivatives - Google Patents

Abstract

  The present invention relates to a 17-hydroxy-17-pentafluoroethyl-estradi-4,9 (10) -dien-11-aryl derivative of general formula (I) having a progesterone antagonism, a process for its preparation, and a derivative thereof. Treatment and / or prevention of various diseases used, and various diseases (particularly uterine fibroids (myoma, uterine leiomyoma)), endometriosis, severe menstrual bleeding, meningiomas, hormone-dependent breast cancer The manufacture of pharmaceutical products for the treatment and / or prevention of complaints associated with menopause, or for birth control and emergency contraception.

Description

  The present invention relates to a 17-hydroxy-17-pentafluoroethyl-estradi-4,9 (10) -dien-11-aryl derivative of general formula (I) having a progesterone antagonism, a process for its preparation, and a derivative thereof. Treatment and / or prevention of various diseases used, and various diseases (particularly uterine fibroids (myoma, uterine leiomyoma)), endometriosis, severe menstrual bleeding, meningiomas, hormone-dependent breast cancer The manufacture of pharmaceutical products for the treatment and / or prevention of complaints associated with menopause, or for birth control and emergency contraception.

  These compounds are valuable active pharmaceutical ingredients, especially for the treatment and / or prevention of uterine fibroids, endometriosis, severe menstrual bleeding, meningiomas, hormone-dependent breast cancer, and menopause complaints It can be used for the production of preparations or pharmaceutical preparations for birth control and emergency contraception. For the treatment of uterine fibroids and endometriosis, the compounds of the invention can also be administered sequentially in combination with a gestagen. In such treatment regimens, the compounds of the invention are administered over a period of 1-6 months, followed by discontinuation of treatment, sequential treatment with gestagens for 2-6 weeks, or oral contraceptives ( Treatment over the same period of time with a combination of oral contraceptives could be performed.

  The effect of the compounds according to the invention as progesterone receptor antagonists has been shown in an in vitro cross-activity test.

  A compound having an antagonistic action on a progesterone receptor (competitive progesterone receptor antagonist) was first known in 1982 (RU 486; European Patent No. 57115), and many reports have been reported since then. Progesterone receptor antagonists with fluorinated 17α side chains were reported in WO 98/34947 and Fuhrmann et al., J. Med. Chem., 43, 5010-5016, 2000.

  Compounds having a fluorinated 17α side chain described in WO 98/34947 generally have a very strong antagonistic activity on the progesterone receptor. Among WO 98/34947 it is very potent and therefore the preferred compound is 11β- (4-acetylphenyl) -20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α -Pregna-4,9-dien-3-one, 11β- (4-acetylphenyl) -20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4-ene -3-one, 6'-acetyl-9,11β-dihydro-17β-hydroxy-17α- (1,1,2,2,2-pentafluoroethyl) -4'H-naphtho [3 ', 2', 1 ′: 10,9,11] ester-4-en-3-one. These compounds are converted to various metabolites in vivo to a considerable extent. Some of them have strong pharmacological activity and others have low pharmacological activity. Metabolism occurs mainly on the 4-substituents of 11-phenyl residues. Various compounds are described in WO 2008/058767, at least some of which are metabolites of the compounds described in WO 98/34947.

  One object of the present invention is to provide a very potent competitive progesterone receptor antagonist, ie to provide an alternative for treating gynecological diseases.

  The compounds of the present invention have been found to be particularly suitable for achieving this purpose.

と、その化合物の塩、その化合物の溶媒和物、前記塩の溶媒和物（その中には、あらゆる結晶多形体、α-、β-、γ-シクロデキストリン・クラトレート、リポソームを用いてカプセル化した前記化合物が含まれる）に関する。ただし、
R¹は、フェニル環とm位またはp位で結合したR^1a基として定義されるか、フェニル環とm位だけで結合したR^1b基として定義され、
R^1aは、(CH₂)_n-R²、C(R³)₂OH、CN、C(CH₂OH)₂R³、C(CH₂OCH₂)R³、

を含むグループの中から選択され、
R^1bは、C₂〜C₁₀-アシル、CHOHアルキルを含むグループの中から選択され、
R²は、アリール、ヘテロアリール、ハロゲン、CN、N₃、OH、NHCONHR⁴、OCONHR⁴、NHCOR⁴を含むグループの中から選択され、
R³は、水素、C₁〜C₁₀-アルキルを含むグループの中から選択され、
R⁴は、水素、C₁〜C₁₀-アルキル、C₂〜C₁₀-アルケニル、C₇〜C₂₀-アラルキル、アリール、ヘテロアリール、(CH₂)_qCO₂R⁵、

を含むグループの中から選択され、
nは、1または2であり、
qは、1〜10であり、
R⁵は、水素、C₁〜C₁₀-アルキル、CH₂OHを含むグループの中から選択され、
Xは、酸素、NOR⁶、NNHSO₂R⁶を含むグループの中から選択され、
Yは、酸素、CHR⁶、NR⁶を含むグループの中から選択され、
R⁶は、水素、C₁〜C₁₀-アルキル、アリール、C₇〜C₂₀-アラルキルを含むグループの中から選択される。 The present invention relates to 17-hydroxy-17-pentafluoroethylestradi-4,9- (10) -dien-11-aryl derivatives of general formula (I):

And salts of the compounds, solvates of the compounds, solvates of the salts, including all crystalline polymorphs, α-, β-, γ-cyclodextrin kralate, liposomes The aforementioned compounds are included). However,
R ¹ is defined as an R ^1a group bonded to the phenyl ring at the m-position or p-position, or is defined as an R ^1b group bonded to the phenyl ring only at the m-position,
R ^1a is (CH ₂ ) _n -R ² , C (R ³ ) ₂ OH, CN, C (CH ₂ OH) ₂ R ³ , C (CH ₂ OCH ₂ ) R ³ ,

Selected from the group containing
R ^1b is selected from the group comprising C ₂ -C ₁₀ -acyl, CHOH alkyl;
R ² is aryl, heteroaryl, are selected from halogen, CN, N _3, OH, from the group including ^{NHCONHR 4, OCONHR 4, NHCOR 4} ,
R ³ is selected from the group comprising hydrogen, C ₁ -C ₁₀ -alkyl,
R ⁴ is hydrogen, C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl, C ₇ -C ₂₀ -aralkyl, aryl, heteroaryl, (CH ₂ ) _q CO ₂ R ⁵ ,

Selected from the group containing
n is 1 or 2,
q is 1 to 10,
R ⁵ is selected from the group comprising hydrogen, C ₁ -C ₁₀ -alkyl, CH ₂ OH,
X is selected from the group comprising oxygen, NOR ⁶ , NNHSO ₂ R ⁶
Y is selected from the group comprising oxygen, CHR ⁶ , NR ⁶
R ⁶ is selected from the group comprising hydrogen, C ₁ -C ₁₀ -alkyl, aryl, C ₇ -C ₂₀ -aralkyl.

  The arrows in the substructures shown above mean the points where these substructures are bonded to the structure of general formula (I).

  The compounds of the general formula (I) according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers) depending on their structure. Accordingly, the present invention includes the enantiomers or diastereomers and their respective mixtures (including racemic mixtures). Components that are uniform as stereoisomers can be separated from the mixture of enantiomers and / or diastereomers in a known manner.

  Each of the above substituents on the steroid backbone can be in either the α-position or the β-position. In addition, a substituent that is on the steroid skeleton chain and contains a double bond, wherein the double bond has at least one substituent that is not hydrogen on each atom, is in the E and Z configurations. Both are possible.

  Where the compounds of the invention can exist in tautomeric forms, all tautomeric forms are included in the invention.

  Preferred salts in the context of the present invention are physiologically compatible salts of the compounds according to the invention. However, salts which are not suitable as pharmaceuticals as they are but can be used for the separation or purification of the compounds according to the present invention are also included in the scope of the present invention.

  If the physiologically compatible salts of the compounds according to the invention contain basic groups, the salts include salts with inorganic or organic acids, in particular salts with mineral acids, carboxylic acids, sulfonic acids. Is included. For example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, There are salts of citric acid, fumaric acid, maleic acid and benzoic acid.

  If the physiologically compatible salts of the compounds according to the invention contain an acidic group, the salts include alkali metal salts, alkaline earth metal salts, ammonium salts, such as the corresponding inorganic or organic bases. The salts that can be obtained by this reaction are included. For example, preferred salts include alkali metal salts (eg, sodium salts, potassium salts), alkaline earth metal salts (eg, calcium salts, magnesium salts), ammonia or ammonium salts derived from organic amines having 1 to 16 carbon atoms. It is done. Examples of organic amines include ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine, N-methyl-glucamine, D-methylglucamine, ethylglucamine, 1,6-hexadiamine, glucosamine, N-methylglycine, 2-amino-1,3-propanediol, tris (hydroxymethyl Aminomethane, 1-amino-2,3,4-butanetriol are preferred.

  Solvate in the context of the present invention means, among the forms of the compounds according to the invention, forms which form adducts with solvent molecules in the solid or liquid state. The solvent can be present in stoichiometric or non-stoichiometric proportions. In the case of stoichiometric solvates, hemi solvates, (semi solvates), mono solvates, sesqui solvates, disolvates, tri solvates, tetra solvates, penta Also called solvate. Hydrates are a special form of solvates in which a conformation with water occurs in the solvate.

  The present invention further includes prodrugs of the compounds according to the invention. The term “prodrug” includes compounds that are converted to the compounds of the invention while in the body, for example, by enzymatic or hydrolysis processes.

  In the context of the present invention, unless otherwise specified, each substituent is defined as follows:

  Alkyl represents a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, n-pentyl, isopentyl. , Neopentyl, hexyl, heptyl, octyl, nonyl, decyl.

Aryl represents a substituted or unsubstituted monocyclic to tricyclic aromatic carbocyclic group such as phenyl and naphthyl, which are halogen (F, Cl, Br, I) group, OH group, O-alkyl group, CO ₂ H group, CO ₂ -alkyl group, NH ₂ group, NH (C ₁ -C ₁₀ -alkyl) group, N (C ₁ -C ₁₀ -alkyl) ₂ group (especially N (CH _{3 2} groups), NO ₂ group, N ₃ group, CN group, C ₁ -C ₁₀ -alkyl group, C ₁ -C ₁₀ -perfluoro-alkyl group, C ₁ -C ₁₀ -acyl group, C ₁ -C ₁₀ -It may be mono- or polysubstituted with an acyloxy group.

  Heteroaryl is a monocyclic ring having generally 5-10, preferably 5-6 ring atoms and having up to 5, preferably up to 4, heteroatoms selected from S, O, N. Or a bicyclic aromatic group such as benzofuranyl, benzothiophenyl, quinolinyl, furyl, imidazolyl, indazolyl, indolyl, isoquinolinyl, oxazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl, pyrazolyl, isoxazolyl, pyrazinyl, quinolyl Tetrazolyl is preferred.

Aralkyl is an aralkyl group that can contain up to 14 carbon atoms in the ring, preferably 6-10 carbon atoms, and 1-8, preferably 1-4 carbon atoms in the alkyl chain. Represent. Useful aralkyl groups are, for example, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, pyridylpropyl. Ring is halogen group, OH group, O-alkyl group, CO ₂ H group, CO ₂ -alkyl group, NH ₂ group, NH (C ₁ -C ₁₀ -alkyl) group, N (C ₁ -C ₁₀ -alkyl) ) ₂ group, NO ₂ group, N ₃ group, CN groups, C ₁ -C ₂₀ - alkyl group, C ₁ -C ₁₀ - perfluoro - alkyl group, C ₁ -C ₂₀ - acyl, C ₁ -C ₂₀ - It can be mono- or polysubstituted with an acyloxy group.

  When a group in a compound according to the invention is substituted, the group can be mono- or polysubstituted unless otherwise indicated. In the context of this invention, all groups which occur more than once are each defined independently of one another. Substitution with the same or different 1, or 2 or 3 substituents is preferred. Substitution with one substituent is particularly preferred.

が好ましい。ただし、
Aは、-O-または-NH-であり、
R⁷は、C₁〜C₄-アルキル、アリル、パラ位が場合によってはC₁〜C₄-アルキル、-CN、C₁〜C₄-アルコキシ、ハロゲン、C₁〜C₄-アルカノイルオキシ、- CO₂H、- CO₂C₁〜₄-アルキル、ピペリジニルのいずれかで置換されたフェニル、

、
ベンジル、-(CH₂)_m-COOR⁸（ここにm=1、2、3のいずれかであり、R⁸=水素またはC₁〜C₄-アルキルである。 Compounds of general formula (II):

Is preferred. However,
A is -O- or -NH-
R ⁷ is C ₁ -C ₄ -alkyl, allyl, where the para position is optionally C ₁ -C ₄ -alkyl, -CN, C ₁ -C ₄ -alkoxy, halogen, C ₁ -C ₄ -alkanoyloxy, _{- CO 2 H, - CO 2} C 1 ~ 4 - alkyl, phenyl substituted with one of piperidinyl,

,
Benzyl, — (CH ₂ ) _m —COOR ⁸ (where m = 1, 2, or 3 and R ⁸ = hydrogen or C ₁ -C ₄ -alkyl.

も同様に好ましい。ただし、
Aは、-O-または-NH-であり、
R⁹は、水素、C₁〜C₄-アルキル、-CN、C₁〜C₄-アルコキシ、ハロゲン、C₁〜C₄-アルカノイルオキシ、- CO₂H、- CO₂C₁〜₄-アルキル、ピペリジルのいずれかである。 Compounds of general formula (III):

Is also preferred. However,
A is -O- or -NH-
R ⁹ is hydrogen, C ₁ -C ₄ - alkyl, -CN, C ₁ ~C ₄ - alkoxy, halogen, C ₁ -C ₄ - _{alkanoyloxy, - CO 2 H, - CO} 2 C 1 ~ 4 - alkyl Or piperidyl.

も好ましい。ただし、
R¹⁰は、場合によってはメチルで置換されたピリジニルまたはチアゾイル、-CN、-OHのいずれかである Compounds of general formula (IV):

Is also preferable. However,
R ¹⁰ is either pyridinyl or thiazoyl optionally substituted with methyl, -CN, -OH

が好ましい。ただし、
R¹¹は、場合によってはヒドロキシルで置換されたC₁〜C₄-アルキル、C₁〜C₄-アルカノイルオキシ、場合によってはメチルで置換されたシクロプロピルのいずれかである。 Furthermore, compounds of general formula (V):

Is preferred. However,
R ¹¹ is either C ₁ -C ₄ -alkyl optionally substituted with hydroxyl, C ₁ -C ₄ -alkanoyloxy, optionally cyclopropyl substituted with methyl.

Yet another preferred compound is:
・ (8S, 11R, 13S, 14S, 17S) -11- (4-Cyclopropylphenyl) -17-hydroxy-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12 , 13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 1),
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-17-pentafluoroethyl-11- [4- (2-pyridin-2-ylethyl) phenyl] -1,2,6, 7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 2),
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-11- {4- [2- (2-methylthiazol-4-yl) ethyl] phenyl} -17-pentafluoroethyl-1 , 2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 3),
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-11- [4- (1-methylcyclopropyl) phenyl] -17-pentafluoroethyl-1,2,6,7, 8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 4),
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-11- [4- (1-hydroxy-1-methylethyl) phenyl] -13-methyl-17-pentafluoroethyl-1,2,6 , 7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 5),
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-11- [4-((1R, 2R or 1S, 2S) -2-hydroxymethylcyclopropyl) phenyl-13-methyl-17-pentafluoro Ethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 6),
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-17-pentafluoroethyl-11- [4- (2-pyridin-3-ylethyl) phenyl] -1,2,6, 7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 7),
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-17-pentafluoroethyl-11- [4- (2-pyridin-4-ylethyl) phenyl] -1,2,6, 7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 8),
3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12 , 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) phenyl] propionitrile (Example 9),
(8S, 11R, 13S, 14S, 17S) -11- (3-acetylphenyl) -17-hydroxy-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12, 13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 10),
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-11- [3-((RS) -1-hydroxyethyl] phenyl] -13-methyl-17-pentafluoroethyl-1,2,6 , 7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 11),
(8S, 11R, 13S, 14S, 17S) -11- (3-Cyclopropylphenyl) -17-hydroxy-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12 , 13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 12),
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-11- [3- (1-methylcyclopropyl) phenyl] -17-pentafluoroethyl-1,2,6,7, 8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 13),
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-11- [3- (2-hydroxyethyl) phenyl] -13-methyl-17-pentafluoroethyl-1,2,6,7,8 , 11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 14),
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-11- [4- (2-hydroxy-1-hydroxymethyl-1-methylethyl) phenyl] -13-methyl-17-pentafluoroethyl- 1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 15),
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-17-pentafluoroethyl-11- [4- (2,2,5-trimethyl- [1,3] dioxane-5- Yl) phenyl] -1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 15),
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-11- [4- (2-hydroxy-1-hydroxymethylethyl) phenyl] -13-methyl-17-pentafluoroethyl-1,2, 6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 16),
1-allyl-3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8 , 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea (Example 18),
1-Isopropyl-3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8 , 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea (Example 19),
1-t-butyl-3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7 , 8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea (Example 20),
・ {3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11, 12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] ureido} acetic acid ethyl ester (Example 21),
3- {3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8, 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] ureido} propionic acid ethyl ester (Example 22),
1-Benzyl-3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8 , 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea (Example 23),
1-phenyl-3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8 , 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea (Example 24),
1- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12 , 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] -3-p-tolylurea (Example 25),
・ {3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11, 12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] ureido} acetic acid (Example 26),
3- {3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8, 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] ureido} propionic acid (Example 27),
・ (8S, 11R, 13S, 14S, 17S) -11- (4-Azidomethylphenyl) -17-hydroxy-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12 , 13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 28),
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-17-pentafluoroethyl-11- [4 '-(1H-tetrazol-5-yl) biphenyl-4-yl] -1 , 2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 29),
4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13, 14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzonitrile (Example 30),
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-17-pentafluoroethyl-11- [4- (1H-tetrazol-5-yl) phenyl] -1,2,6, 7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 31),
1- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12 , 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] -3- (4-methoxyphenyl) urea (Example 32),
1- (4-fluorophenyl) -3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3, 6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea (Example 33),
1- (4-Chlorophenyl) -3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6 , 7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea (Example 34),
1- (4-t-butylphenyl) -3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2, 3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea (Example 35),
4- {3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8, 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] ureido} benzoic acid ethyl ester (Example 36),
1- [4- (3,5-Dimethylisoxazol-4-yl) phenyl] -3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3 -Oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea (Example 37),
4- {3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8, 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] ureido} benzoic acid (Example 38),
1- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12 , 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] -3- (4-piperidin-1-ylphenyl) urea (Example 39),
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-11- [4- (3-methyloxetan-3-yl) phenyl] -17-pentafluoroethyl-1,2,6 , 7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 40),
Ethylcarbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12 , 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 41),
・ Isopropylcarbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12 , 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 42),
Allylcarbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12 , 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 43),
T-Butylcarbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11 , 12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 44),
(4-piperidin-1-ylphenyl) carbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3, 6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 45),
Phenylcarbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12 , 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 46),
(4-Methoxyphenyl) carbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7, 8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 47),
(4-Methylphenyl) carbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7, 8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 48),
(4-Fluorophenyl) carbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7, 8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 49),
・ (4-Chlorophenyl) carbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8 , 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 50),
(4-t-Butylphenyl) carbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6, 7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 51),
4- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12 , 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyloxycarbonylamino] benzoic acid ethyl ester (Example 52),
[4- (3,5-Dimethylisoxazol-4-yl) phenyl] carbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17 -Pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 53) ,
N- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12 , 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] nicotinamide (Example 54),
3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12 , 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyloxycarbonylamino] propionic acid (Example 55),
Benzylcarbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12 , 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 56),
3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12 , 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyloxycarbonylamino] propionic acid ethyl ester (Example 57).

Some of the very potent progesterone receptor antagonists described in this document have less than 50% oral bioavailability expected in humans, making them useful for local administration that requires low systemic stability. Especially suitable. Examples include the compounds shown in Examples 2-9, 15, 17, 23, 24, 40, 41 (see Tables 1 and 2).

  The individual definitions given above for a particular combination of groups, or groups contained in a preferred combination, can be replaced with other combinations of group definitions, if desired, regardless of the particular combination of groups.

  A combination of two or more of the above preferred ranges is particularly preferred.

  It has been found that the compounds or derivatives of the present invention have excellent progesterone antagonism. In some clinical trials, treatment with progesterone receptor antagonists (mifepristone, asoprisnil, proelex) may lead to a significant reduction in uterine fibroma and a significant reduction in symptoms associated with uterine fibroma It was found that there is sex. Furthermore, clinical trials have shown that symptoms (particularly pain) caused by endometriosis can be clearly reduced during treatment with the above-described progesterone receptor antagonists.

The invention further relates to a process for preparing the derivatives of general formula (I) according to the invention. Such derivatives can be prepared as shown in Scheme 1 with the epoxides of general formula (VI) (where X ′ is an oxygen atom, two alkoxy groups OR ⁷ , linear or branched C ₂ -C ₁₀ -alkylene-α, ω-dioxy group,
R ⁷ is C ₁ -C ₄ -alkyl) by an organometallic coupling reaction (preferably a Grignard reaction catalyzed by copper) (wherein R ¹ and X ′ are each As defined above,
R ⁸ is hydrogen,
R ⁹ is a hydroxyl group, or
R ⁸ , R ⁹ are combined to form a bond) to convert any functional group present in R ¹ and / or perform further conversion reactions to obtain compounds of general formula (I ′) Release X group, sometimes defined as oxygen, and / or remove water (R ⁸ = hydrogen, R ⁹ = hydroxyl group) to form a double bond (R ⁸ , R ⁹ together Can optionally be prepared by further functionalizing the carbonyl group (X = oxygen) (X = NOR ⁶ or NNHSO ₂ R ⁶ ).

Scheme 1

When R ⁸ and R ⁹ are combined into a bond within the structure of general formula (I ′), these groups can be formed in various proportions to each other during the described reaction. Possible double bond isomers (I′-A), (I′-B), (I′-C) are represented.

  As an example, some possible reaction sequences starting from compounds of general formula (VI) to give compounds of general formula (I ′) are shown in detail in scheme 2.

Conversion of a compound of general formula (VI) to a compound of general formula (VII), or a compound of general formula (I ′) (where X ′, R ³ , R ⁸ , R ⁹ are as defined above, respectively) The direct conversion to) is done by organometallic coupling reactions (copper-catalyzed Grignard reactions are preferred) by methods known to those skilled in the art. Typical examples of the details can be found in Examples 2d, 4b, 5c, 10a, 12b, 13b, 14b, 15a, 16a, 40a.

The compound of general formula (VIII) (wherein X ′, R ³ , R ⁸ , R ⁹ are as defined above) is converted into the compound of general formula (VII) by methods known to those skilled in the art. Can be prepared by oxidative cleavage of double bonds. Typical examples of the details can be found in Examples 2c and 5b.

Compounds of general formula (IX) (wherein R ^X is hydroxyl, azide, amine and X ′, R ³ , R ⁸ , R ⁹ are as defined above) are known to those skilled in the art. Can be prepared from compounds of general formula (VIII) by reduction of the carbonyl group, substitution of the azide and reduction to the amine. Typical details of such reaction sequences can be found in Examples 17b, 17c, 17d.

Compounds of general formula (X) wherein R ^y is aryl, heteroaryl, CN and X ′, R ³ , R ⁸ , R ⁹ are as defined above are known to those skilled in the art. Can be prepared from compounds of general formula (VIII) by the Horner-Wittig reaction or the Wittig reaction. Typical examples of the details can be found in Examples 2b, 3b, 7b, 8b, 9b.

  Alternatively, the compound of the general formula (X) can be prepared from the compound of the general formula (VII) by a metathesis reaction using a transition metal catalyst (preferably a ruthenium-based catalyst). A typical example of the details can be found in Example 6b.

  Compounds of general formula (X) can be converted to compounds of general formula (I ′) by double bond, for example hydrogenation, cyclopropanation, epoxidation. Typical examples of the details can be found in Examples 2a, 3a, 6a, 7a, 8a, 9a.

  The compound of general formula (VIII) can be converted to the compound of general formula (I ′) by, for example, nitrile formation, alkylation, or reduction. Typical examples of the details can be found in Examples 5, 5a and 30a.

  The compound of the general formula (VII) can be converted to the compound of the general formula (I ′) by any of double bonds such as hydrogenation, cyclopropanation, epoxidation and borohydride. Typical examples of the details can be found in Examples 1a, 4a, 12a, 13a, 14a.

The compound of the general formula (IX) (wherein R ^X is a hydroxyl group or an amino group) is further converted into any of carbamate, amide, and urea by a method known to those skilled in the art, A compound of I ′) can be obtained. Typical examples of the details can be found in Examples 17a-25a, 32a-39a, 41a-53a, 54a, 55b, 56, 57.

If not yet finished by the above reaction, any ketal present in the compound of general formula (I ′), (VII), (VIII), (IX), (X) is cleaved to give general formula (X ′) And / or if R ⁸ is hydrogen and R ⁹ is hydroxyl, water is removed. Typical examples of the details can be found in Examples 1 to 10 and 12 to 57.

  The functional groups present in the compounds of the general formulas (I), (I ′), (VII), (VIII), (IX), (X) can be further brought about by methods known to those skilled in the art. Examples include esterification of carboxyl groups, hydrolysis of carboxylic esters or carboxamides, formation of nitriles from carboxylic acids or aldehydes, preparation of tetrazoles from nitriles or carboxylic acids. Some typical examples of its details can be found in Examples 11, 26a, 27a, 29a, 31a, 55a.

  Except where the preparation of the starting compound is described in this specification, the compound is known to those skilled in the art, or is prepared in a manner similar to known compounds or methods described herein. Can do. A mixture of isomers can be separated into individual compounds by conventional methods (eg crystallization, chromatography, salt formation).

  The preparation of the salt is done in the usual way by adding the same or excess amount of base or acid (which may be in solution form) to the solution of the compound of general formula (I), optionally separating the precipitate, The solution is worked up in the usual way.

  The resulting compound of general formula (I) is optionally reacted with a suitable (i) solvent and / or (ii) a base or acid to give a solvate of the compound and / or a salt of the compound And / or solvates of said salts.

  The above general definitions for groups or the definitions given within the preferred ranges apply to both the final product of general formula (I) and the starting materials or intermediates necessary for their respective preparation.

  The compounds of the present invention exhibit unexpected and unexpected pharmacological, pharmacokinetic and pharmacodynamic action profiles.

  The compounds of the invention are therefore suitable for use as pharmaceutical products for the treatment and / or prevention of human and animal diseases.

  The pharmaceutical effect of a compound according to the invention can be explained by its action as a progesterone receptor antagonist, ie by its antagonism on the progesterone receptor.

  The invention further provides for the treatment and / or prevention of diseases based on hormone-dependent hyperproliferative processes, preferably gynecological diseases, in particular uterine fibroma, endometriosis, hormone-dependent breast cancer, using the compounds according to the invention. Treatment and / or prevention is provided.

  The present invention further provides treatment and / or prevention of various diseases (particularly the above-mentioned diseases) using the compounds according to the present invention.

  The present invention further provides a compound of the present invention for use in a method of treating and / or preventing uterine fibroma, endometriosis, hormone dependent breast cancer.

  The present invention further provides the use of the compounds of the present invention for the manufacture of a medicament for treating and / or preventing various diseases (particularly the above-mentioned diseases).

  The present invention further provides methods for treating and / or preventing various diseases (particularly the above-mentioned diseases). At that time, in the treatment and contraception of uterine fibroma or endometriosis, the compound of the present invention is used in an amount of 0.1-100 mg per patient per day, and tumor diseases (eg meningiomas, hormone-dependent tumors (eg breast cancer)) For emergency contraception, the compound of the present invention is used in an amount of 0.1 to 500 mg per patient per day.

  The invention further provides a pharmaceutical product comprising at least one compound according to the invention and at least one or more other active ingredients, in particular for the treatment and / or prevention of the abovementioned diseases.

  For the treatment of tumor diseases, for example, the following active ingredients / classes of active ingredients: SERM and / or SERD and / or antiestrogens and / or aromatase inhibitors and / or kinase inhibitors and / or blood vessels An angiogenesis inhibitor and / or a cytostatic can be administered simultaneously or sequentially.

  For the treatment of uterine fibroma or endometriosis, the compounds of the invention can be administered simultaneously or sequentially in combination with a gestagen or in combination with an estrogen and gestagen combination.

  WO 96/15794 (Spicer et al., Balance Farm), WO 96/03130 (Stockemann et al., Schering), PCT / EP2009 / 003249 (Moller et al., Bayer Schering Pharma) and progesterone receptor antagonist / Gestagen therapy is disclosed. A regimen (possibly repeated) of administering a gestagen over a period of 1 to 4 weeks after a progesterone receptor antagonist is administered over a period of 2 to 4 months is a treatment for treating uterine fibroma and endometriosis Very suitable. It is particularly appropriate to administer the progesterone receptor antagonist for 84 days followed by gestagen for 14 days (and possibly repeat).

  One option for the treatment of complaints associated with menopause is to administer the compounds of the invention simultaneously or sequentially, eg in combination with SERM, SERD, gestagen.

  SERMs (selective estrogen receptor modulators) are tissue-selective compounds that exert antiestrogenic or estrogenic effects, for example to suppress estrogen effects in the uterus, but neutral or estrogenic effects in bone Effect. Examples are clomiphene, raloxifene, tamoxifen, trimifene, bazedoxifene, lasofoxifene, olmeroxifene.

  Selective estrogen receptor destabilizers (SERDs) are drugs that antagonize the estrogen receptor ("pure antiestrogens" without an estrogen active ingredient) and reduce the activity of that receptor (e.g. fulvestrant, ZK-703, ZK-253 (Hoffmann J. et al., J. Natl. Cancer Inst., 2004, 96, pp. 210-218)), WO 98/007740, WO 99/33855, WO 03/045972 Reduce the activity of the compounds described in.

  Antiestrogens are compounds that antagonize the estrogen receptor, such as fulvestrant.

  Since the aromatase inhibitor suppresses the enzyme aromatase, it suppresses androgen from becoming an estrogen by aromatization. Aromatase inhibitors include, among others, anastrozole, letrozole, exemestane, borozole, formestane, and fadrozole.

  Kinase inhibitors are enzymes that transfer phosphate residues from ATP to other substrates, especially the hydroxyl groups there. Examples are sorafenib (Nexavar), imatinib (Gleevec).

  Angiogenesis inhibitors (eg, Avastin) reduce or prevent blood supply to the tumor, thereby reducing or preventing blood supply to the tumor.

  Cytostatics (eg cisplatin, taxol, taxotere, sagopirone, ixabepilone) are natural or synthetic substances that inhibit cell growth and division.

  A gestagen in the context of the present invention is either natural progesterone itself or a synthetic derivative, binds to a progesterone receptor like progesterone itself, and suppresses ovulation at doses exceeding the ovulation inhibitory dose. Examples of synthetic derivatives include drospirenone, guestden, levonorgestrel, cyproterone acetate, desogestrel, 3-ketodesogestrel, noretisterone, noretisterone acetate, and dienogest.

  The combination of gestagen and estrogen is a combination of active ingredients contained in known oral contraceptives (for example, Yasmin, femoban, tricular, malberon, YAZ, etc.).

  The compounds of the invention can act systemically and / or locally. For that purpose, the compounds according to the invention can be administered by suitable routes or used as implants or stents. The routes include, for example, oral, intrauterine, intravaginal, parenteral, lung, nasal cavity, sublingual, tongue, buccal, rectal, skin, transdermal, conjunctival, and ear.

  “Intrauterine” means in particular administered by IUS (intrauterine system) or IUD (intrauterine fear). One method of intravaginal administration is in particular by IVR / VRS (intravaginal ring / vaginal ring system).

Forms for intrauterine or intravaginal administration (eg WO 01/47490, especially page 1, page 10-5, line 13, and page 7, pages 19-58, line 6; for vaginal rings, WO 06 / 010097, particularly page 10, lines 22-14, line 28) can contain the compounds of the invention and non-silicone and / or silicone polymers, in particular siloxane-based elastomers. (See WO 01/47490, especially page 7, lines 19-15, line 15).

  Through these routes of administration, the compounds of the invention can be administered in suitable dosage forms.

  Forms suitable for oral administration include a compound of the invention in crystalline and / or amorphous form and / or dissolved form, releasing the compound of the invention rapidly and / or in a modified state. By doing so, it is a form that functions as in the prior art. Forms include, for example, tablets (uncoated tablets or coated tablets, tablets with an enteric coating, delayed dissolution coating, insoluble coating that controls the release of the compounds according to the invention), tablets or films / wafers that disintegrate rapidly in the oral cavity, There are films / lyophilizates, capsules (eg hard gelatin capsules or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols, solutions.

  Parenteral administration is performed while avoiding the absorption step (eg intravenous route, intraarterial route, intracardiac route, intravertebral route, intralumbar route) or including absorption (eg intramuscular route) , Subcutaneous route, intradermal route, percutaneous route, intraperitoneal route). Dosage forms suitable for parenteral administration include preparations for injection and infusions in the form of solutions, suspensions, emulsions, lyophilizates, sterile powders.

  With regard to other routes of administration, for example inhalation medicaments (including powder inhalers, nebulizers), nasal solutions, solutions, sprays; tablets, films / wafers or capsules for administration into the tongue, sublingual, oral cavity Suppositories, preparations for the ears or eyes, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg patches), milk, pastes, foam Dust powder, implants and stents are suitable.

  The compounds of the invention can be converted into the stated administration forms. This can be done in a known manner by mixing with inert non-toxic excipients suitable for pharmaceuticals. As excipients, in particular carrier substances (eg microcrystalline cellulose, lactose, mannitol), solvents (eg liquid polyethylene glycol), emulsifiers, dispersants, wetting agents (eg sodium dodecyl sulfate, polyoxysorbitan oleate), binders (E.g. polyvinylpyrrolidone), synthetic and natural polymers (e.g. albumin), stabilizers (e.g. ascorbic acid as an antioxidant), colored substances (e.g. iron oxide as an inorganic pigment), taste and / or scent regulators, etc. is there.

  Further according to the present invention, there is provided a medicament comprising at least one compound according to the present invention, usually together with one or more inert non-toxic excipients suitable for medicaments, and of the pharmaceutical product for the above purpose. Usage is provided.

  In some cases, however, the above amounts may have to be avoided depending on the body weight, route of administration, individual response to the active ingredient, type of preparation, time of administration, and interval of administration. Therefore, in some cases, less than the above minimum amount may be sufficient, while the above upper limit may have to be exceeded. If larger amounts are to be administered, it may be recommended to divide into several individual doses throughout the day.

  Unless otherwise noted,% in the following tests and examples are percentages by weight and parts are parts by weight. Solvent ratios, dilution rates, and concentration values for liquid / solution are always based on volume.

  The following examples serve to illustrate the invention, but the invention is in no way limited to these examples.

Example 1
(8S, 11R, 13S, 14S, 17S) -11- (4-Cyclopropylphenyl) -17-hydroxy-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12, 13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one

  A solution of 266 mg (0.44 mmol) of the compound prepared according to Example 1a in 14 ml of acetone was mixed with 0.65 ml of 4N hydrochloric acid and the resulting mixture was stirred at 23 ° C. for 20 minutes. The mixture is poured into saturated sodium bicarbonate solution, extracted repeatedly with dichloromethane, the combined organic extracts are dried over sodium sulfate, and the residue obtained after filtration and solvent removal is purified by chromatography. did. 173 mg of the title compound was isolated as a colorless foam (78%).

  1H NMR (CDCl3): δ = 0.61 (3H), 0.66 (2H), 0.94 (2H), 1.41-1.55 (2H), 1.74-1.89 (4H), 2.03 (1H), 2.05 (1H), 2.24-2.63 (9H), 2.73 (1H), 4.41 (1H), 5.77 (1H), 6.97 (2H), 7.04 (2H) ppm.

Example 1a
(5R, 8S, 11R, 13S, 14S, 17S) -11- (4-Cyclopropylphenyl) -5 ', 5', 13-trimethyl-17- (pentafluoroethyl) -1,2,3,4, 6,7,8,11,12,13,14,15,16,17-Tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -5,17-diol

  A solution of 300 mg (0.5 mmol) of the compound prepared according to Example 2d in 30 ml of diethyl ether is mixed with 27 ml of ethereal diazomethane solution at 3 ° C. and a total of 131 mg of palladium (II) acetate and 5 portions. Mix over minutes. The mixture was stirred for 15 minutes and then purified by chromatography. 266 mg of the title compound was isolated as a colorless foam (87%).

Example 2
(8S, 11R, 13S, 14S, 17S) -17-Hydroxy-13-methyl-17-pentafluoroethyl-11- [4- (2-pyridin-2-ylethyl) phenyl] -1,2,6,7 , 8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one

  Conversion of 60 mg (89 μmol) of the compound prepared according to Example 2a in the same way as Example 1 gave 36.6 mg (72%) of the title compound as a colorless foam after work-up and purification.

  1H NMR (CDCl3): δ = 0.63 (3H), 1.44 to 1.61 (2H), 1.77 to 1.92 (3H), 2.10 (1H), 2.24 to 2.69 (10H), 2.78 (1H), 2.99 to 3.16 (4H) 4.46 (1H), 5.82 (1H), 7.03-7.18 (6H), 7.58 (1H), 8.58 (1H) ppm.

Example 2a
(5R, 8S, 11R, 13S, 14S, 17S) -5 ', 5', 13-Trimethyl-17- (pentafluoroethyl) -11- {4-[(E) -2- (pyridin-4-yl) ) Ethyl] phenyl} -1,2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2'- [1,3] Dioxane] -5,17-diol

  A solution of 70 mg (0.1 mmol) of the compound prepared according to Example 2b in 1 ml ethanol was mixed with 5 mg palladium on carbon (10%) and hydrogenated under a hydrogen atmosphere. After filtration and solvent removal, 70 mg of the title compound was isolated (100%). It was further converted without purification.

Example 2b
(5R, 8S, 11R, 13S, 14S, 17S) -5 ', 5', 13-Trimethyl-17- (pentafluoroethyl) -11- {4-[(E) -2- (pyridin-2-yl ) Ethenyl] phenyl} -1,2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2'- [1,3] Dioxane] -5,17-diol

  A solution of 345 mg of diethyl pyridin-2-ylmethylphosphonate in 10 ml of tetrahydrofuran was mixed with 0.6 mg of a 1.6 molar solution of n-butyllithium in hexane at −10 ° C., and the resulting mixture was brought to 23 ° C. And stirred for 1.5 hours. The mixture is then cooled to -70 ° C., a solution of 300 mg (0.5 mmol) of the compound prepared according to example 2c in 5 ml of tetrahydrofuran is added dropwise, the cooling bath is removed and the mixture is left to stand for 1.5%. Reacted over time. The mixture was poured into saturated ammonium chloride solution, extracted repeatedly with ethyl acetate, and the combined organic extracts were dried over sodium sulfate. The residue obtained after filtration and solvent removal was purified by chromatography. 302 mg of the title compound was isolated as a colorless foam (89%).

Example 2c
4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-5 ', 5', 13-trimethyl-17-pentafluoroethyl-2,3,4,5,6,7 , 8,11,12,13,14,15,16,17-Tetradecahydro-1H-spiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) -benzaldehyde

  A solution of 3.99 g (6.69 mmol) of the compound prepared according to Example 2d in 200 ml of tetrahydrofuran was added to 25 ml of water, 1 ml of triethylamine, 3.2 ml of saturated sodium bicarbonate solution and 3.2 g of sodium periodate. And 2.7 ml of a 40 mmol solution of osmium tetroxide in t-butanol, and the resulting mixture was stirred at 23 ° C. Addition of the oxidizing agent was repeated after 16 hours and 40 hours, and after another 24 hours, the solid components were filtered out. It was rinsed with ethyl acetate and the combined organic phases were washed with half-saturated sodium thiosulfate solution and saturated sodium chloride solution. The residue obtained after filtration and solvent removal was purified by crystallization from diisopropyl ether. The title compound was isolated as a colorless foam, 3.56g (89%).

Example 2d
(5R, 8S, 11R, 13S, 14S, 17S) -11- (4-ethenylphenyl) -5 ', 5', 13-trimethyl-17- (pentafluoroethyl) -1,2,3,4, 6,7,8,11,12,13,14,15,16,17-Tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -5,17-diol

  Prepare a Grignard reagent using 2.22 g of magnesium shavings and a solution of 11.95 ml of 4-bromostyrene in 75 ml of tetrahydrofuran, weakly heated to 30-50 ° C and optionally adding iodine crystals did. The mixture is cooled to 5 ° C., 117 mg of copper (I) chloride are added and 15 g (30.5 mmol) of (5R, 8S, 10R, 13S, 14S, 17S) prepared by the method described in DE 102006054535 -17- (pentafluoroethyl) -5,10-epoxy-5 ', 5', 13-trimethyl-1,2,3,4,6,7,8,12,13,14,15,16,17 -A 150 ml solution containing tridecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -17-ol was added dropwise. The mixture was stirred at 23 ° C. for an additional hour, diluted with ethyl acetate and poured into saturated ammonium chloride solution. The aqueous phase was extracted repeatedly with ethyl acetate and the combined organic extracts were washed with saturated sodium chloride solution and dried over sodium sulfate. The solid obtained after filtration and solvent removal was recrystallized from hexanes to isolate 16.6 g (91%) of the title compound as a colorless solid.

Example 3
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-11- {4- [2- (2-methylthiazol-4-yl) ethyl] phenyl} -17-pentafluoroethyl-1, 2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one

  Converting 7 mg (10 μmol) of the compound prepared according to Example 3a in the same way as Example 1 gave 5 mg (84%) of the title compound as a colorless foam after work-up and purification.

  1H NMR (CDCl3): δ = 0.59 (3H), 1.41-1.54 (2H), 1.74-1.85 (3H), 2.01-2.11 (2H), 2.24-2.63 (9H), 2.70 (3H), 2.73 (1H) 2.93-3.04 (4H), 4.42 (1H), 5.78 (1H), 6.61 (1H), 7.06 (2H), 7.09 (2H) ppm.

Example 3a
(5R, 8S, 11R, 13S, 14S, 17S) -5 ', 5', 13-Trimethyl-11- {4- [2- (2-methyl-1,3-thiazol-4-yl) ethyl] phenyl } -17- (pentafluoroethyl) -1,2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3 , 2 '-[1,3] Dioxane] -5,17-diol

  Converting 48 mg (69 μmol) of the compound prepared according to Example 3b as in Example 2a, converted 8 mg of the title compound as a colorless foam (19%) after work-up and purification.

Example 3b
(5R, 8S, 11R, 13S, 14S, 17S) -5 ', 5', 13-trimethyl-11- {4-[(E / Z) -2- (2-methyl-1,3-thiazol-4 -Yl) ethyl] phenyl} -17- (pentafluoroethyl) -1,2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -5,17-diol

  Analogously to Example 2b, 500 mg (0.84 mmol) of the compound prepared according to Example 2c was converted with diethyl (2-methylthiazol-4-ylmethyl) phosphonate to give the title compound after work-up and purification. Isolated as a colorless foam, 479 mg (83%).

Example 4
(8S, 11R, 13S, 14S, 17S) -17-Hydroxy-13-methyl-11- [4- (1-methylcyclopropyl) phenyl] -17-pentafluoroethyl-1,2,6,7,8 , 11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one

  Conversion of 160 mg (0.26 mmol) of the compound prepared according to Example 4a in the same way as Example 1 gave 70.6 mg (53%) of the title compound as a colorless foam after work-up and purification.

  1H NMR (CDCl3): δ = 0.60 (3H), 0.70 to 0.77 (2H), 0.79 to 0.87 (2H), 1.38 (3H), 1.40 to 1.55 (2H), 1.72 to 1.86 (3H), 2.01 to 2.11 ( 2H), 2.24 to 2.63 (9H), 2.73 (1H), 4.41 (1H), 5.77 (1H), 7.05 (2H), 7.12 (2H) ppm.

Example 4a
(5R, 8S, 11R, 13S, 14S, 17S) -5 ', 5', 13-Trimethyl-11- [4- (1-methylcyclopropyl) phenyl] -17- (pentafluoroethyl) -1,2 , 3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -5 , 17-diol

  Converting 200 mg (0.33 mmol) of the compound prepared according to Example 4b in the same way as Example 1a converted 165 mg of the title compound as a colorless foam (81%) after work-up and purification.

Example 4b
(5R, 8S, 11R, 13S, 14S, 17S) -5 ', 5', 13-Trimethyl-17- (pentafluoroethyl) -11- [4- (prop-1-en-2-yl) phenyl] -1,2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] Dioxane] -5,17-diol

Analogously to Example 2d, 5 g (10.2 mmol) of (5R, 8S, 10R, 13S, 14S, 17S) -17- (pentafluoroethyl) -5,10 prepared by the method described in DE 102006054535 -Epoxy-5 ', 5', 13-trimethyl-1,2,3,4,6,7,8,12,13,14,15,16,17-tridecahydrospiro [cyclopenta [a] phenanthrene- Reaction of 3,2 '-[1,3] dioxane] -17-ol with Grignard reagent prepared from 10 g of 1-bromo-4-isopropenylbenzene yielded the title compound after work-up and purification. Isolated 4.01 g as a colorless foam (65%).

Example 5
(8S, 11R, 13S, 14S, 17S) -17-Hydroxy-11- [4- (1-hydroxy-1-methylethyl) phenyl] -13-methyl-17-pentafluoroethyl-1,2,6, 7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one

  Converting 20 mg (32 micromoles) of the compound prepared according to Example 5a in the same way as Example 1 gave 7.6 mg (46%) of the title compound as a colorless foam after work-up and purification.

  1H NMR (CD2Cl2): δ = 0.59 (3H), 1.40 to 1.62 (2H), 1.52 (6H), 1.71 to 1.87 (3H), 1.98 to 2.11 (2H), 2.19 to 1.63 (10H), 2.73 (1H) 4.45 (1H), 5.71 (1H), 7.16 (2H), 7.38 (2H) ppm.

Example 5a
(5R, 8S, 11R, 13S, 14S, 17S) -11- [4- (2-Hydroxypropan-2-yl) phenyl] -5 ', 5', 13-trimethyl-17- (pentafluoroethyl)- 1,2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane ] -5,17-diol

  A solution of 23 mg (38 micromoles) of the compound prepared according to Example 5b in 1.6 ml of tetrahydrofuran was mixed with 200 μl of a 1.6 molar solution of methyllithium in diethyl ether at 0 ° C. and stirred for 45 minutes. The mixture was poured into saturated ammonium chloride solution and extracted repeatedly with ethyl acetate, and the combined organic extracts were washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration and solvent removal, 23 mg of the title compound was isolated as a colorless foam (97%). It was further converted without purification.

Example 5b
1- {4-[(5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-5 ′, 5 ′, 13-trimethyl-17- (pentafluoroethyl) -1,2,4, 5,6,7,8,11,12,13,14,15,16,17-Tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl] Phenyl} ethanone

  Converting 5.5 g (9.0 mmol) of the compound prepared according to Example 5c in the same way as Example 2c, after work-up and purification, 4.78 g of the title compound was isolated as a colorless solid (87%) .

Example 5c
(5R, 8S, 11R, 13S, 14S, 17S) -5 ', 5', 13-Trimethyl-17- (pentafluoroethyl) -11- [4- (prop-1-en-2-yl) phenyl] -1,2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] Dioxane] -5,17-diol

  Analogously to Example 2d, 5 g (10.2 mmol) of (5R, 8S, 10R, 13S, 14S, 17S) -17- (pentafluoroethyl) -5,10 prepared by the method described in DE 102006054535 -Epoxy-5 ', 5', 13-trimethyl-1,2,3,4,6,7,8,12,13,14,15,16,17-tridecahydrospiro [cyclopenta [a] phenanthrene- Reaction of 3,2 '-[1,3] dioxane] -17-ol with Grignard reagent prepared from 10 g of 1-bromo-4-isopropenylbenzene yielded the title compound after work-up and purification. Isolated 4.01 g as a colorless foam (65%).

Example 6
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-11- [4-((1R, 2R) -2-hydroxymethylcyclopropyl) phenyl-13-methyl-17-pentafluoroethyl-1,2 , 6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (A) and (8S, 11R, 13S, 14S, 17S) -17 -Hydroxy-11- [4-((1S, 2S) -2-hydroxymethylcyclopropyl) phenyl-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13, 14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (B)

  In analogy to example 1, 22 mg (35 μmol) of the compound prepared according to example 6a are reacted and after work-up and purification 3.5 mg of the title compound A or B is isolated as a colorless foam ( 19%), 7.9 mg of the title compound B or A was isolated as a colorless foam (42%).

  1H NMR of A or B (CDCl3): δ = 0.60 (3H), 0.96 (2H), 1.39 to 1.53 (3H), 1.73 to 1.89 (4H), 2.03 (1H), 2.05 (1H), 2.16 (1H) 2.23 to 2.63 (9H), 2.72 (1H), 4.05 (2H), 4.41 (1H), 5.77 (1H), 6.97 (2H), 7.06 (2H) ppm.

  1H NMR of B or A (CDCl3): δ = 0.60 (3H), 0.93 (2H), 1.37 to 1.55 (4H), 1.72 to 1.86 (4H), 2.05 (1H), 2.11 (1H), 2.23 to 2.63 ( 9H), 2.72 (1H), 3.62 (2H), 4.41 (1H), 5.77 (1H), 6.96 (2H), 7.05 (2H) ppm.

Example 6a
(5R, 8S, 11R, 13S, 14S, 17S) -11- [4-((1R, 2R) -2-hydroxymethylcyclopropyl) phenyl] -5 ', 5', 13-trimethyl-17-pentafluoro Ethyl-1,2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3 ] Dioxane] -5,17-diol (A) and (5R, 8S, 11R, 13S, 14S, 17S) -11- [4-((1S, 2S) -2-hydroxymethylcyclopropyl) phenyl] -5 ', 5', 13-Trimethyl-17-pentafluoroethyl-1,2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [ a] phenanthrene-3,2 '-[1,3] dioxane] -5,17-diol (B)

  Converting 272 mg (0.43 mmol) of the compound prepared according to Example 6b in the same way as Example 1a, after work-up and purification, 25 mg of a mixture of the two title compounds was isolated as a colorless foam (11 %).

Example 6b
(5R, 8S, 11R, 13S, 14S, 17S) -11- {4-[(1E) -3-Hydroxyprop-1-en-1-yl] phenyl} -5 ', 5', 13-trimethyl- 17- (pentafluoroethyl) -1,2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] Dioxane] -5,17-diol

  A solution of 1.0 g (1.68 mmol) of the compound prepared according to Example 2d in 16.5 ml dichloromethane was added to 0.57 ml allyl alcohol and 145 mg [[1,3-bis (2,4,6-trimethylphenyl) -2. -Imidazolidinyl] methyl] dichloro (phenylmethylene) (tricyclohexylphosphoranyl) ruthenium and heated under reflux for 4.5 hours. The mixture was purified by chromatography to isolate the title compound as a colorless foam, 163 mg (16%).

Example 7
(8S, 11R, 13S, 14S, 17S) -17-Hydroxy-13-methyl-17-pentafluoroethyl-11- [4- (2-pyridin-3-ylethyl) phenyl] -1,2,6,7 , 8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one

  Converting 54 mg (80 μmol) of the compound prepared according to Example 7a in the same way as Example 1, after work-up and purification, 16.3 mg of the title compound was isolated as a colorless foam (36%).

  1H NMR (CDCl3): δ = 0.59 (3H), 1.39 to 1.57 (2H), 1.71 to 1.87 (3H), 2.05 (1H), 2.21 to 2.63 (10H), 2.73 (1H), 2.90 (4H), 4.40 (1H), 5.77 (1H), 6.99 (2H), 7.03 (2H), 7.19 (1H), 7.43 (1H), 8.24 (1H), 8.39 (1H) ppm.

Example 7a
(5R, 8S, 11R, 13S, 14S, 17S) -11- [4- (2-Pyridin-3-ylethyl) phenyl] -5 ', 5', 13-trimethyl-17-pentafluoroethyl-1,2 , 3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -5 , 17-diol

  Conversion of 57 mg (85 μmol) of the compound prepared according to Example 7b in the same way as Example 2a gave 54 mg (94%) of the title compound as a colorless foam after work-up and purification.

Example 7b
(5R, 8S, 11R, 13S, 14S, 17S) -5 ', 5', 13-Trimethyl-17- (pentafluoroethyl) -11- {4-[(E / Z) -2- (pyridine-3 -Yl) ethenyl] phenyl} -1,2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] Dioxane] -5,17-diol

  Analogously to Example 2b, 250 mg (0.42 mmol) of the compound prepared according to Example 2c was converted using diethyl pyridin-3-ylmethylphosphonate to give the title compound as a colorless foam after work-up and purification. 170 mg was isolated (60%).

Example 8
(8S, 11R, 13S, 14S, 17S) -17-Hydroxy-13-methyl-17-pentafluoroethyl-11- [4- (2-pyridin-4-ylethyl) phenyl] -1,2,6,7 , 8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one

  Conversion of 80 mg (0.12 mmol) of the compound prepared according to Example 8a in the same way as Example 1 gave 23 mg (34%) of the title compound as a colorless foam after work-up and purification.

  1H NMR (CDCl3): δ = 0.57 (3H), 1.36 to 1.89 (5H), 2.05 (1H), 2.20 to 2.65 (9H), 2.73 (1H), 2.90 (4H), 3.00 (1H), 4.41 (1H ), 5.77 (1H), 6.92 to 7.11 (6H), 8.40 (2H) ppm.

Example 8a
(5R, 8S, 11R, 13S, 14S, 17S) -11- [4- (2-Pyridin-4-ylethyl) phenyl] -5 ', 5', 13-trimethyl-17-pentafluoroethyl-1,2 , 3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -5 , 17-diol

  Conversion of 82 mg (0.12 mmol) of the compound prepared according to Example 8b in the same way as Example 2a gave 80 mg (97%) of the title compound as a colorless foam after work-up and purification.

Example 8b
(5R, 8S, 11R, 13S, 14S, 17S) -5 ', 5', 13-Trimethyl-17- (pentafluoroethyl) -11- {4-[(E / Z) -2- (pyridine-4 -Yl) ethenyl] phenyl} -1,2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] Dioxane] -5,17-diol

  Analogously to Example 2b, 200 mg (0.33 mmol) of the compound prepared according to Example 2c was converted with diethyl pyridin-4-ylmethylphosphonate to give the title compound as a colorless foam after work-up and purification. 182 mg was isolated (81%).

Example 9
3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) phenyl] propionitrile

  Conversion of 70 mg (0.11 mmol) of the compound prepared according to Example 9a in the same way as Example 1 gave 46.3 mg of the title compound as a colorless foam (79%) after work-up and purification.

  1H NMR (CDCl3): δ = 0.59 (3H), 1.39 to 1.55 (2H), 1.72 to 1.86 (3H), 2.01 to 2.11 (2H), 2.21 to 2.65 (11H), 2.74 (1H), 2.92 (2H) 4.43 (1H), 5.78 (1H), 7.15 (4H) ppm.

Example 9a
3- [4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-5 ′, 5 ′, 13-trimethyl-17-pentafluoroethyl-2,3,4,5, 6,7,8,11,12,13,14,15,16,17-Tetradecahydro-1H-spiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl ) Phenyl] propionitrile

  Conversion of 300 mg (0.48 mmol) of the compound prepared according to Example 9b in the same manner as Example 2a gave 197 mg of the title compound as a colorless foam (65%) after work-up and purification.

Example 9b
(2E / Z) -3- {4-[(5R, 8S, 11R, 13S, 14S, 17S) -5,17-Dihydroxy-5 ', 5', 13-trimethyl-17- (pentafluoroethyl)- 1,2,4,5,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane ] -11-yl] phenyl} prop-2-enonitrile

  Analogously to Example 2b, 1.0 g (1.67 mmol) of the compound prepared according to Example 2c was converted with diethyl cyanomethylphosphonate to give 961 mg of the title compound as a colorless foam after work-up and purification. (93%).

Example 10
(8S, 11R, 13S, 14S, 17S) -11- (3-Acetylphenyl) -17-hydroxy-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13 , 14,15,16,17-Dodecahydrocyclopenta [a] phenanthren-3-one

  In a manner similar to Example 1, 15.9 g (22.7 mmol) of the compound prepared according to Example 10a was converted, and after work-up and purification, 7.92 g of the title compound was isolated as a crystalline solid (69% ).

  1H NMR (CDCl3): δ = 0.57 (3H), 1.40 to 1.57 (2H), 1.73 to 1.88 (3H), 2.08 (1H), 2.17 (1H), 2.19 to 2.67 (9H), 2.59 (3H), 2.73 (1H), 4.50 (1H), 5.79 (1H), 7.35-7.41 (2H), 7.75 (1H), 7.85 (1H) ppm.

Example 10a
(5R, 8S, 11R, 13S, 14S, 17S) -3,3-Dimethoxy-13-methyl-17-pentafluoroethyl-11- [3- (2,5,5-trimethyl- [1,3] dioxane -2-yl) phenyl] -1,2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] Dioxane] -5,17-diol

  14 g (28.4 mmol) of (5R, 8S, 10R, 13S, 14S, 17S) -17- (pentafluoroethyl) -5,10 prepared by the method described in DE 102006054535 as in Example 2d -Epoxy-5 ', 5', 13-trimethyl-1,2,3,4,6,7,8,12,13,14,15,16,17-tridecahydrospiro [cyclopenta [a] phenanthrene- Reaction of 3,2 '-[1,3] dioxane] -17-ol with Grignard reagent prepared from 33.1 g of 2- (3-bromophenyl) -2,5,5-trimethyl-1,3-dioxane Allowed 17.7 g (89%) of the title compound as a colorless foam after work-up and purification.

Example 11
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-11- [3-((RS) -1-hydroxyethyl] phenyl] -13-methyl-17-pentafluoroethyl-1,2,6, 7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one

  A solution of 100 mg (0.2 mmol) of the compound prepared according to Example 10 in 1.5 ml isopropanol was mixed with 5.5 mg yttrium (III) isopropoxide and heated to 95 ° C. for 6 hours. The mixture was concentrated and the residue was purified by chromatography. 54 mg of the title compound was isolated as a colorless foam (53%).

  1H NMR (CDCl3): δ = 0.54 (3H), 1.30 to 1.53 (3H), 1.48 (3H), 1.55 to 2.15 (8H), 2.19 to 2.56 (6H), 4.16 to 4.40 (2H), 4.87 (1H) 5.52 + 5.54 (1H), 7.09 (1H), 7.14 (1H), 7.22 (1H), 7.27 (1H) ppm.

Example 12
(8S, 11R, 13S, 14S, 17S) -11- (3-Cyclopropylphenyl) -17-hydroxy-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12, 13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one

  Converting 108 mg (0.17 mmol) of the compound prepared according to Example 12a in the same way as Example 1 gave 50 mg (59%) of the title compound as a colorless foam after work-up and purification.

1H NMR (CDCl3): δ = 0.61 (3H), 0.65 (2H), 0.96 (2H), 1.41 to 1.56 (2H), 1.75 to 1.90 (4H), 2.02 to 2.11 (2H), 2.24 to 2.63 (9H) 2.73 (1H), 4.41 (1H), 5.78 (1H), 6.81 (1H), 6.91 (1H), 6.94 (1H), 7.14 (1H) ppm.

Example 12a
(5R, 8S, 11R, 13S, 14S, 17S) -11- (3-cyclopropylphenyl) -5 ', 5', 13-trimethyl-17- (pentafluoroethyl) -1,2,3,4, 6,7,8,11,12,13,14,15,16,17-Tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -5,17-diol

  Conversion of 100 mg (0.17 mmol) of the compound prepared according to Example 12b in the same way as Example 1a gave 100 mg of the title compound as a colorless foam (98%) after work-up and purification.

Example 12b
(5R, 8S, 11R, 13S, 14S, 17S) -11- (3-ethenylphenyl) -5 ', 5', 13-trimethyl-17- (pentafluoroethyl) -1,2,3,4, 6,7,8,11,12,13,14,15,16,17-Tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -5,17-diol

  15 g (30.5 mmol) of (5R, 8S, 10R, 13S, 14S, 17S) -17- (pentafluoroethyl) -5,10 prepared by the method described in DE 102006054535 in analogy to example 2d -Epoxy-5 ', 5', 13-trimethyl-1,2,3,4,6,7,8,12,13,14,15,16,17-tridecahydrospiro [cyclopenta [a] phenanthrene- 3,2 ′-[1,3] Dioxane] -17-ol was reacted with Grignard reagent prepared from 12 ml of 3-bromostyrene to give 16.6 the title compound as a colorless foam after work-up and purification. g Isolated (92%).

Example 13
(8S, 11R, 13S, 14S, 17S) -17-Hydroxy-13-methyl-11- [3- (1-methylcyclopropyl) phenyl] -17-pentafluoroethyl-1,2,6,7,8 , 11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one

  In a manner similar to Example 1, 110 mg (0.18 mmol) of the compound prepared according to Example 13a was converted, and after work-up and purification, 50 mg of the title compound was isolated as a colorless foam (55%).

  1H NMR (CDCl3): δ = 0.60 (3H), 0.74 (2H), 0.81 (2H), 1.38 (3H), 1.42 to 1.55 (2H), 1.75 to 1.86 (3H), 2.02 to 2.11 (2H), 2.23 ~ 2.64 (9H), 2.73 (1H), 4.43 (1H), 5.79 (1H), 6.93 (1H), 7.03 (1H), 7.07 (1H), 7.17 (1H) ppm.

Example 13a
(5R, 8S, 11R, 13S, 14S, 17S) -5 ', 5', 13-Trimethyl-11- [3- (1-methylcyclopropyl) phenyl] -17- (pentafluoroethyl) -1,2 , 3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -5 , 17-diol

  Conversion of 100 mg (0.16 mmol) of the compound prepared according to Example 13b in the same way as Example 1a gave 100 mg of the title compound as a colorless foam (98%) after work-up and purification.

Example 13b
(5R, 8S, 11R, 13S, 14S, 17S) -11- (3-Isopropenylphenyl) -5 ', 5', 13-trimethyl-17- (pentafluoroethyl) -1,2,3,4, 6,7,8,11,12,13,14,15,16,17-Tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -5,17-diol

  5.9 g (12.0 mmol) of (5R, 8S, 10R, 13S, 14S, 17S) -17- (pentafluoroethyl) -5, prepared as described in Example 2d by the method described in DE 102006054535, 10-epoxy-5 ', 5', 13-trimethyl-1,2,3,4,6,7,8,12,13,14,15,16,17-tridecahydrospiro [cyclopenta [a] phenanthrene -3,2 '-[1,3] dioxane] -17-ol was reacted with Grignard reagent prepared from 11.9 g of 1-bromo-3-isopropenylbenzene, and after work-up and purification, the title 5.36 g of the compound was isolated as a colorless foam (73%).

Example 14
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-11- [3- (2-hydroxyethyl) phenyl] -13-methyl-17-pentafluoroethyl-1,2,6,7,8, 11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one

  Conversion of 1.50 mg (81 μmol) of the compound prepared according to Example 14a in the same way as Example 1 gave 31.2 mg of the title compound as a colorless foam after work-up and purification (75%) .

  1H NMR (CDCl3): δ = 0.59 (3H), 1.41-1.55 (2H), 1.74-1.86 (3H), 2.06 (1H), 2.20-2.64 (10H), 2.74 (1H), 2.85 (2H), 3.51 (1H), 3.84 (2H), 4.43 (1H), 5.78 (1H), 7.00 (1H), 7.04 (1H), 7.08 (1H), 7.22 (1H) ppm.

Example 14a
(5R, 8S, 11R, 13S, 14S, 17S) -5 ', 5', 13-trimethyl-11- [3- (2-hydroxyethyl) phenyl] -17- (pentafluoroethyl) -1,2, 3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -5, 17-diol

  To a solution of 500 mg (0.84 mmol) of the compound prepared according to Example 14b in 5 ml of tetrahydrofuran was added dropwise 6.3 ml of a 0.5 molar solution of 9-borabicyclo [3.3.1] nonane in tetrahydrofuran. The mixture was stirred at 23 ° C. for 4 hours. The mixture was cooled to 3 ° C., 2.8 ml of 5% sodium hydroxide solution and 0.72 ml of 30% hydrogen peroxide solution were added, and the resulting mixture was stirred overnight. It was extracted repeatedly with ethyl acetate, washed with water and saturated sodium thiosulfate solution and dried over sodium sulfate. The residue obtained after filtration and solvent removal was purified by chromatography. 346 mg of the title compound was isolated as a colorless foam (67%).

Example 14b
(5R, 8S, 11R, 13S, 14S, 17S) -11- (3-ethenylphenyl) -5 ', 5', 13-trimethyl-17- (pentafluoroethyl) -1,2,3,4, 6,7,8,11,12,13,14,15,16,17-Tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -5,17-diol

  15 g (30.5 mmol) of (5R, 8S, 10R, 13S, 14S, 17S) -17- (pentafluoroethyl) -5,10 prepared by the method described in DE 102006054535 in analogy to example 2d -Epoxy-5 ', 5', 13-trimethyl-1,2,3,4,6,7,8,12,13,14,15,16,17-tridecahydrospiro [cyclopenta [a] phenanthrene- 3,2 ′-[1,3] Dioxane] -17-ol was reacted with Grignard reagent prepared from 12 ml of 3-bromostyrene to give 16.6 the title compound as a colorless foam after work-up and purification. g Isolated (92%).

Example 15
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-11- [4- (2-hydroxy-1-hydroxymethyl-1-methylethyl) phenyl] -13-methyl-17-pentafluoroethyl-1 , 2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (A) and (8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-17-pentafluoroethyl-11- [4- (2,2,5-trimethyl- [1,3] dioxan-5-yl) phenyl] -1,2,6,7 , 8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (B)

  In the same manner as in Example 1, 200 mg (290 μmol) of the compound prepared according to Example 15a was converted to 55 mg (35%) of the title compound A and 40 mg (35%) of the title compound B after work-up and purification. 24%), each isolated as a colorless foam.

  1H NMR (CDCl3) of A: δ = 0.58 (3H), 1.27 (3H), 1.38 to 1.57 (2H), 1.71 to 1.87 (3H), 1.99 to 2.18 (3H), 2.27 (1H), 2.22 to 2.64 ( 9H), 2.74 (1H), 3.81 (2H), 3.95 (2H), 4.43 (1H), 5.78 (1H), 7.17 (2H), 7.33 (2H) ppm.

  1H NMR (CDCl3) of B: δ = 0.59 (3H), 1.41 (3H), 1.44 (3H), 1.48 (3H), 1.36 to 1.56 (2H), 1.74 to 1.85 (3H), 2.01 to 2.10 (2H) 2.25-2.63 (9H), 2.74 (1H), 3.73 (2H), 4.09 (2H), 4.43 (1H), 5.78 (1H), 7.14 (2H), 7.25 (2H) ppm.

Example 15a
(5R, 8S, 11R, 13S, 14S, 17S) -5 ', 5', 13-Trimethyl-17-pentafluoroethyl-11- [4- (2,5,5-trimethyl- [1,3] dioxane -2-yl) phenyl] -2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydro-1H-spiro [cyclopenta [a] phenanthrene-3, 2 '-[1,3] Dioxane] -5,17-diol

  Similar to Example 2d, 500 mg (1.02 mmol) of (5R, 8S, 10R, 13S, 14S, 17S) -17- (pentafluoroethyl) -5,10 prepared by the method described in DE 102006054535 -Epoxy-5 ', 5', 13-trimethyl-1,2,3,4,6,7,8,12,13,14,15,16,17-tridecahydrospiro [cyclopenta [a] phenanthrene- 3,2 '-[1,3] Dioxane] -17-ol was prepared using freshly prepared 4- (2,5,5-trimethyl- [1,3] dioxan-2-yl) phenylmagnesium bromide Upon conversion, after work-up and purification, 617 mg of the title compound was isolated as a colorless foam (87%).

Example 16
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-11- [4- (2-hydroxy-1-hydroxymethylethyl) phenyl] -13-methyl-17-pentafluoroethyl-1,2,6 , 7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one

  Converting 200 mg (290 μmol) of the compound prepared according to Example 16a in the same way as Example 1, 74 mg of the title compound was isolated as a colorless foam (47%) after work-up and purification.

  1H NMR (CDCl3): δ = 0.58 (3H), 1.40 to 1.57 (2H), 1.70 to 1.89 (3H), 2.05 (1H), 2.13 to 2.66 (12H), 2.73 (1H), 3.07 (1H), 3.84 ~ 4.06 (4H), 4.43 (1H), 5.78 (1H), 7.14 (4H) ppm.

Example 16a
(5R, 8S, 11R, 13S, 14S, 17S) -5 ', 5', 13-Trimethyl-17-pentafluoroethyl-11- [4- (5,5-dimethyl- [1,3] dioxane-2 -Yl) phenyl] -2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydro-1H-spiro [cyclopenta [a] phenanthrene-3,2 ' -[1,3] Dioxane] -5,17-diol

  Analogously to Example 2d, 1.4 g (2.84 mmol) of (5R, 8S, 10R, 13S, 14S, 17S) -17- (pentafluoroethyl) -5, prepared by the method described in DE 102006054535, 10-epoxy-5 ', 5', 13-trimethyl-1,2,3,4,6,7,8,12,13,14,15,16,17-tridecahydrospiro [cyclopenta [a] phenanthrene -3,2 '-[1,3] dioxane] -17-ol is converted using freshly prepared 4- (5,5-dimethyl- [1,3] dioxan-2-yl) phenylmagnesium bromide This gave 1.43 g (73%) of the title compound as a colorless foam after work-up and purification.

Example 17
1-ethyl-3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8, 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea

  Converting 44 mg (up to 67 μmol) of the compound prepared according to Example 17a in the same way as Example 1 gave 16 mg of the title compound as a colorless foam (43%) after work-up and purification.

  1H NMR (CDCl3): δ = 0.57 (3H), 1.07 (3H), 1.36 to 1.56 (2H), 1.71 to 1.89 (3H), 2.05 (1H), 2.14 to 2.64 (9H), 2.70 (1H), 3.09 ~ 3.24 (3H), 4.20 (1H), 4.29 (1H), 4.40 (1H), 4.60 (1H), 4.91 (1H), 5.75 (1H), 7.10 (2H), 7.15 (2H) ppm.

Example 17a
1- [4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ′, 5 ′, 13-trimethyl-1,2,3,4, 6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) benzyl] -3-ethylurea

  A solution of 40 mg (67 μmol) of the compound prepared according to Example 17b in 0.5 ml of dichloromethane was mixed with 5.5 μl of ethyl isocyanate and stirred at 23 ° C. for 1 hour. The mixture was concentrated and the resulting crude product was further converted without purification.

Example 17b
(5R, 8S, 11R, 13S, 14S, 17S) -11- (4-Aminomethylphenyl) -17-pentafluoroethyl-5 ′, 5 ′, 13-trimethyl-1,2,3,4,6, 7,8,11,12,13,14,15,16,17-Tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -5,17-diol

  A solution of 1.8 g (2.88 mmol) of the compound prepared according to Example 17c in 50 ml of tetrahydrofuran was mixed with 8 ml of water and 0.56 ml of trimethylphosphine and stirred at 23 ° C. for 4 hours. 6 ml of 25% ammonia solution was added and the resulting mixture was stirred at 23 ° C. for an additional 16 hours and then concentrated. The title compound obtained as a crude product was further converted without purification.

Example 17c
(5R, 8S, 11R, 13S, 14S, 17S) -11- (4-Azidomethylphenyl) -17-pentafluoroethyl-5 ', 5', 13-trimethyl-1,2,3,4,6, 7,8,11,12,13,14,15,16,17-Tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -5,17-diol

  A solution of 2.0 g (3.33 mmol) of the compound prepared according to Example 17d in 50 ml of tetrahydrofuran was added at 3 ° C. with 1 ml of diphenylphosphoryl azide and 0.58 ml of 1,8-diazabicyclo [5.4.0] undes-7-ene. After mixing, the resulting mixture was reacted at 23 ° C. for 4 hours, and further reacted at 60 ° C. for 16 hours. Water was added to this mixture and extracted repeatedly with ethyl acetate, and the combined organic extracts were washed with saturated sodium chloride solution and dried over sodium sulfate. The residue obtained after filtration and solvent removal was purified by chromatography. 1.85 g of the title compound was isolated as a colorless foam (89%).

Example 17d
(5R, 8S, 11R, 13S, 14S, 17S) -11- (4-Hydroxymethylphenyl) -17-pentafluoroethyl-5 ′, 5 ′, 13-trimethyl-1,2,3,4,6, 7,8,11,12,13,14,15,16,17-Tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -5,17-diol

  A solution of 2.0 g (3.34 mmol) of the compound prepared according to Example 2c in 12 ml tetrahydrofuran and 1.2 ml methanol was mixed with 70 mg sodium borohydride at 3 ° C. and stirred for 2.5 hours. The mixture was poured into saturated ammonium chloride solution and extracted repeatedly with ethyl acetate, and the combined organic extracts were washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration and solvent removal, 2.0 g of the title compound was isolated as a colorless foam (100%). It was further converted without purification.

Example 18
1-allyl-3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8, 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea

  Conversion of the crude product prepared according to Example 18a as in Example 1 gave 18.6 mg (48%) of the title compound as a colorless foam after work-up and purification.

1H NMR (CDCl3): δ = 0.58 (3H), 1.37 to 1.56 (2H), 1.71 to 1.88 (3H), 2.05 (1H), 2.16 to 2.64 (9H), 2.65 to 2.77 (2H), 3.78 (2H) 4.22 to 4.37 (2H), 4.42 (1H), 4.61 (1H), 4.86 (1H), 5.08 (1H), 5.14 (1H), 5.76 (1H), 5.82 (1H), 7.11 (2H), 7.17 ( 2H) ppm.

Example 18a
1-allyl-3- [4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ', 5', 13-trimethyl-1,2, 3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11- Yl) benzyl] urea

  Analogously to Example 17a, 40 mg (67 micromol) of the compound prepared according to Example 17b were converted using allyl isocyanate. The crude product isolated after work-up was further converted without purification.

Example 19
1-isopropyl-3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8, 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea

  Conversion of the crude product prepared according to Example 19a as in Example 1 gave 16.9 mg (43%) of the title compound as a colorless foam after work-up and purification.

  1H NMR (CDCl3): δ = 0.58 (3H), 1.11 (6H), 1.37 to 1.56 (2H), 1.72 to 1.88 (3H), 2.05 (1H), 2.16 to 2.64 (9H), 2.71 (1H), 2.81 (1H), 3.83 (1H), 4.19-4.36 (3H), 4.41 (1H), 4.69 (1H), 5.76 (1H), 7.11 (2H), 7.17 (2H) ppm.

Example 19a
1-isopropyl-3- [4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-1,2,3,4,6,7,8, 11,12,13,14,15,16,17-Tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) benzyl] urea

  Analogously to Example 17a, 40 mg (67 μmol) of the compound prepared according to Example 17b were converted using isopropyl isocyanate. The crude product isolated after work-up was further converted without purification.

Example 20
1-t-butyl-3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7, 8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea

  Conversion of the crude product prepared according to Example 20a as in Example 1 gave 18.4 mg (46%) of the title compound as a colorless foam after work-up and purification.

  1H NMR (CDCl3): δ = 0.58 (3H), 1.31 (9H), 1.39 to 1.56 (2H), 1.72 to 1.87 (3H), 2.05 (1H), 2.17 to 2.63 (10H), 2.71 (1H), 4.18 ~ 4.34 (3H), 4.42 (1H), 4.53 (1H), 5.77 (1H), 7.11 (2H), 7.18 (2H) ppm.

Example 20a
1-t-butyl-3- [4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ', 5', 13-trimethyl-1, 2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane]- 11-yl) benzyl] urea

  Analogously to Example 17a, 40 mg (67 μmol) of the compound prepared according to Example 17b were converted using t-butyl isocyanate. The crude product isolated after work-up was further converted without purification.

Example 21
{3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12 , 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] ureido} acetic acid ethyl ester

  Conversion of the crude product prepared according to Example 21a as in Example 1 gave 16.7 mg (40%) of the title compound as a colorless foam after work-up and purification.

  1H NMR (CDCl3): δ = 0.57 (3H), 1.26 (3H), 1.37 to 1.55 (2H), 1.71 to 1.87 (3H), 2.05 (1H), 2.17 to 2.63 (9H), 2.66 (1H), 2.71 (1H), 3.90-4.06 (3H), 4.13-4.24 (2H), 4.31 (1H), 4.42 (1H), 5.06 (2H), 5.77 (1H), 7.11 (2H), 7.18 (2H) ppm.

Example 21a
{3- [4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ', 5', 13-trimethyl-1,2,3,4 , 6,7,8,11,12,13,14,15,16,17-Tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) benzyl ] Ureido} acetic acid ethyl ester

  Analogously to Example 17a, 40 mg (67 μmol) of the compound prepared according to Example 17b were converted using ethyl isocyanatoacetate. The crude product isolated after work-up was further converted without purification.

Example 22
3- {3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11 , 12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] ureido} propionic acid ethyl ester

  The crude product prepared according to Example 22a was converted in the same manner as in Example 1, and after work-up and purification, 16.4 mg of the title compound was isolated as a colorless foam (38%).

  1H NMR (CDCl3): δ = 0.58 (3H), 1.25 (3H), 1.38 to 1.56 (2H), 1.71 to 1.88 (3H), 2.05 (1H), 2.17 to 2.65 (11H), 2.71 (1H), 2.74 (1H), 3.44 (2H), 4.09 (1H), 4.14 (1H), 4.20-4.35 (2H), 4.42 (1H), 4.82 (1H), 5.05 (1H), 5.77 (1H), 7.11 (2H) 7.17 (2H) ppm.

Example 22a
3- {3- [4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ', 5', 13-trimethyl-1,2,3 , 4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl ) Benzyl] ureido} propionic acid ethyl ester

  Analogously to Example 17a, 40 mg (67 μmol) of the compound prepared according to Example 17b was converted with ethyl 3-isocyanatopropionate. The crude product isolated after work-up was further converted without purification.

Example 23
1-benzyl-3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8, 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea

  The crude product prepared according to Example 23a was converted in the same manner as in Example 1, and after work-up and purification, 19.1 mg of the title compound was isolated as a colorless foam (45%).

  1H NMR (CDCl3): δ = 0.56 (3H), 1.38 to 1.55 (2H), 1.71 to 1.87 (3H), 2.05 (1H), 2.13 to 2.63 (10H), 2.69 (1H), 4.21 to 4.36 (4H) 4.40 (1H), 4.80-4.89 (2H), 5.75 (1H), 7.09 (2H), 7.14 (2H), 7.20-7.33 (5H) ppm.

Example 23a
1-benzyl-3- [4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ', 5', 13-trimethyl-1,2, 3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11- Yl) benzyl] urea

  Analogously to Example 17a, 40 mg (67 μmol) of the compound prepared according to Example 17b was converted with benzyl isocyanate. The crude product isolated after work-up was further converted without purification.

Example 24
1- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] -3-phenylurea

  Conversion of the crude product prepared according to Example 24a as in Example 1 gave 18.7 mg (46%) of the title compound as a colorless foam after work-up and purification.

  1H NMR (CDCl3): δ = 0.54 (3H), 1.37 to 1.54 (2H), 1.70 to 1.87 (3H), 2.03 (3H), 2.11 to 2.61 (9H), 2.66 (1H), 2.82 (1H), 4.20 ~ 4.43 (3H), 5.58 (1H), 5.75 (1H), 7.00 (1H), 7.07 (2H), 7.14 (2H), 7.21 to 7.30 (5H) ppm.

Example 24a
1- [4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ′, 5 ′, 13-trimethyl-1,2,3,4, 6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) benzyl] -3-phenylurea

  Analogously to Example 17a, 40 mg (67 micromol) of the compound prepared according to Example 17b was converted with phenyl isocyanate. The crude product isolated after work-up was further converted without purification.

Example 25
1- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] -3-p-tolylurea

  Conversion of the crude product prepared according to Example 25a as in Example 1 gave 14.6 mg (35%) of the title compound as a colorless foam after work-up and purification.

  1H NMR (CD3OD): δ = 0.58 (3H), 1.35 to 1.57 (2H), 1.69 to 1.84 (3H), 2.09 (1H), 2.15 to 2.47 (5H), 2.25 (3H), 2.53 to 2.73 (4H) 2.79 (1H), 4.33 (2H), 4.51 (1H), 5.73 (1H), 7.04 (2H), 7.17-7.28 (6H) ppm.

Example 25a
1- [4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ′, 5 ′, 13-trimethyl-1,2,3,4, 6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) benzyl] -3-p-tolylurea

  Analogously to Example 17a, 40 mg (67 μmol) of the compound prepared according to Example 17b were converted using 4-tolyl isocyanate. The crude product isolated after work-up was further converted without purification.

Example 26
{3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12 , 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] ureido} acetic acid

  Conversion of 58 mg (83 μmol) of the compound prepared according to Example 26a in the same way as Example 1 gave 22 mg of the title compound as a colorless foam (45%) after work-up and purification.

  1H NMR (CD3OD): δ = 0.57 (3H), 1.36 to 1.54 (2H), 1.70 to 1.82 (3H), 2.09 (1H), 2.16 to 2.46 (5H), 2.55 to 2.72 (4H), 2.79 (1H) 3.70 (2H), 4.26 (2H), 4.50 (1H), 5.73 (1H), 7.17 (2H), 7.22 (2H) ppm.

Example 26a
{3- [4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ', 5', 13-trimethyl-1,2,3,4 , 6,7,8,11,12,13,14,15,16,17-Tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) benzyl ] Ureido} acetic acid

  A solution of 85 mg (120 μmol) of the compound prepared according to Example 21a in a mixture of 1 ml of tetrahydrofuran and 1 ml of ethanol was mixed with 1 ml of 5% aqueous lithium hydroxide solution and stirred at 23 ° C. for 3 hours. The mixture was diluted with water, acidified with 1 molar hydrochloric acid, saturated with sodium chloride, extracted repeatedly with diethyl ether, and the combined organic extracts were dried over sodium sulfate. After filtration and solvent removal, 64 mg of the title compound was isolated as a colorless foam (78%).

Example 27
3- {3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11 , 12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] ureido} propionic acid

Conversion of 62 mg (87 μmol) of the compound prepared according to Example 27a in the same manner as in Example 1 gave 22 mg (42%) of the title compound as a colorless foam after work-up and purification.

  1H NMR (CD3OD): δ = 0.57 (3H), 1.36 to 1.54 (2H), 1.70 to 1.82 (3H), 2.09 (1H), 2.16 to 2.45 (7H), 2.55 to 2.71 (4H), 2.79 (1H) 3.35 (2H), 4.24 (2H), 4.49 (1H), 5.73 (1H), 7.18 (4H) ppm.

Example 27a
3- {3- [4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ', 5', 13-trimethyl-1,2,3 , 4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl ) Benzyl] ureido} propionic acid

  Analogously to Example 26a, 87 mg (120 micromoles) of the compound prepared according to Example 22a were converted to isolate 68 mg of the title compound as a colorless foam (81%) after work-up.

Example 28
(8S, 11R, 13S, 14S, 17S) -11- (4-Azidomethylphenyl) -17-hydroxy-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12, 13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one

  Conversion of 50 mg (80 μmol) of the compound prepared according to Example 17c in the same way as Example 1 gave 26.6 mg (64%) of the title compound as a colorless foam after work-up and purification.

  1H NMR (CDCl3): δ = 0.58 (3H), 1.39 to 1.58 (2H), 1.72 to 1.88 (3H), 2.00 to 2.16 (2H), 2.20 to 2.66 (9H), 2.74 (1H), 4.31 (2H) 4.46 (1H), 5.79 (1H), 7.16 (2H), 7.24 (2H) ppm.

Example 29
(8S, 11R, 13S, 14S, 17S) -17-Hydroxy-13-methyl-17-pentafluoroethyl-11- [4 '-(1H-tetrazol-5-yl) biphenyl-4-yl] -1, 2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one

  Converting 63 mg (88 μmol) of the compound prepared according to Example 29a in the same manner as in Example 1 yielded 18 mg (34%) of the title compound as a colorless foam after work-up and purification.

  1H NMR (CD3OD): δ = 0.65 (3H), 1.39 to 1.60 (2H), 1.72 to 1.85 (3H), 2.11 (1H), 2.24 to 2.49 (5H), 2.58 to 2.77 (4H), 2.85 (1H) 4.58 (1H), 5.75 (1H), 7.34 (2H), 7.62 (2H), 7.69 (2H), 8.07 (2H) ppm.

Example 29a
(5R, 8S, 11R, 13S, 14S, 17S) -5 ', 5', 13-Trimethyl-17-pentafluoroethyl-11- [4 '-(1H-tetrazol-5-yl) biphenyl-4-yl ] -2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydro-1H-spiro [cyclopenta [a] phenanthrene-3,2 '-[1, 3] Dioxane] -5,17-diol

  300 mg (0.45 mmol) of (5R, 8S, 11R, 13S, 14S, 17S) -5 ′, 5 ′, 13-trimethyl-17-pentafluoroethyl-11- [prepared by the method described in DE 19706061 4'-Cyanobiphenyl-4-yl] -2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydro-1H-spiro [cyclopenta [a] phenanthrene A suspension consisting of -3,2 '-[1,3] dioxane] -17-ol, 570 mg sodium azide, 15 mg ammonium chloride and 6 ml dimethylformamide was added at a bath temperature of 150 ° C. for 16 hours. Heated. The mixture was concentrated, placed in a 1: 1 mixture of dichloromethane and ethanol, filtered through celite, and the concentrated filtrate was purified by chromatography. The title compound was isolated as a colorless foam, 63 mg (20%).

Example 30
4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14 , 15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzonitrile

  Converting 50 mg (84 μmol) of the compound prepared according to Example 30a as in Example 1, 24 mg of the title compound was isolated as a colorless foam (58%) after work-up and purification.

  1H NMR (CDCl3): δ = 0.55 (3H), 1.40 to 1.56 (2H), 1.74 to 1.89 (3H), 2.08 (1H), 2.16 (1H), 2.17 to 2.65 (9H), 2.71 (1H), 4.48 (1H), 5.81 (1H), 7.32 (2H), 7.59 (2H) ppm.

Example 30a
4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-5 ', 5', 13-trimethyl-17-pentafluoroethyl-2,3,4,5,6,7 , 8,11,12,13,14,15,16,17-Tetradecahydro-1H-spiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) benzonitrile

  A suspension of 505 mg (0.84 mmol) of the compound prepared according to Example 2c in 2.6 ml of 25% aqueous ammonia is mixed with 10 ml of tetrahydrofuran and 669 mg of iodine and heated to a bath temperature of 60 ° C. for 21 hours. did. The mixture was extracted with ethyl acetate, washed with water, half-saturated sodium thiosulfate solution and saturated sodium chloride solution, dried over sodium sulfate, and the residue obtained after filtration and solvent removal was chromatographed on silica gel. Purified by 434 mg of the title compound was isolated as a colorless foam (86%).

Example 31
(8S, 11R, 13S, 14S, 17S) -17-Hydroxy-13-methyl-17-pentafluoroethyl-11- [4- (1H-tetrazol-5-yl) phenyl] -1,2,6,7 , 8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one

  Conversion of 26 mg (41 μmol) of the compound prepared according to Example 31a as in Example 1 yielded 8.1 mg of the title compound as a colorless foam (37%) after work-up and purification.

  1H NMR (CD3OD): δ = 0.64 (3H), 1.38 to 1.60 (2H), 1.71 to 1.86 (3H), 2.12 (1H), 2.22 to 2.49 (5H), 2.56 to 2.79 (4H), 2.85 (1H) , 4.58 (1H), 5.76 (1H), 7.34 (2H), 7.94 (2H) ppm.

Example 31a
(5R, 8S, 11R, 13S, 14S, 17S) -5 ', 5', 13-Trimethyl-17-pentafluoroethyl-11- [4- (1H-tetrazol-5-yl) phenyl] -2,3 , 4,6,7,8,11,12,13,14,15,16,17-tetradecahydro-1H-spiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane]- 5,17-diol

  Converting 100 mg (0.17 mmol) of the compound prepared according to Example 30a in the same way as Example 29a, 27 mg of the title compound was isolated as a colorless foam (25%) after work-up and purification.

Example 32
1- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] -3- (4-methoxyphenyl) urea

  Converting 50 mg (67 micromol) of the compound prepared according to Example 32a as in Example 1, converted 21 mg of the title compound as a colorless foam (49%) after work-up and purification.

  1H NMR (CDCl3): δ = 0.56 (3H), 1.37 to 1.54 (2H), 1.72 to 1.86 (3H), 2.04 (1H), 2.15 to 2.62 (9H), 2.66 (1H), 2.70 (1H), 3.77 (3H), 4.34 (2H), 4.40 (1H), 5.19 (1H), 5.76 (1H), 6.49 (1H), 6.82 (2H), 7.06-7.19 (6H) ppm.

Example 32a
1- [4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ′, 5 ′, 13-trimethyl-1,2,3,4, 6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) benzyl] -3- (4-methoxyphenyl) urea

  A solution of 40 mg (67 μmol) of the compound prepared according to Example 17b in 1 ml dichloromethane was mixed with 9 μl 4-methoxyphenyl isocyanate and stirred at 23 ° C. for 2 hours. The mixture was concentrated and the resulting residue was further converted without purification.

Example 33
1- (4-Fluorophenyl) -3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6 , 7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea

  Converting 49 mg (67 μmol) of the compound prepared according to Example 33a in the same way as Example 1 gave 21 mg (50%) of the title compound as a colorless foam after work-up and purification.

  1H NMR (CDCl3): δ = 0.54 (3H), 1.36 to 1.54 (2H), 1.71 to 1.88 (3H), 2.04 (1H), 2.10 to 2.72 (10H), 2.88 (1H), 4.27 (2H), 4.39 (1H), 5.59 (1H), 5.75 (1H), 6.90 (2H), 7.02-7.24 (7H) ppm.

Example 33a
1- [4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ′, 5 ′, 13-trimethyl-1,2,3,4, 6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) benzyl] -3- (4-fluorophenyl) urea

  Analogously to Example 32a, 40 mg (67 μmol) of the compound prepared according to Example 17b was converted with 4-fluorophenyl isocyanate to give 50 mg of the title compound as a crude product after work-up. It was.

Example 34
1- (4-chlorophenyl) -3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6, 7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea

  Converting 50 mg (66 μmol) of the compound prepared according to Example 34a as in Example 1, converted 21 mg of the title compound as a colorless foam (50%) after work-up and purification.

  1H NMR (CDCl3): δ = 0.51 (3H), 1.34 to 1.51 (2H), 1.67 to 1.82 (3H), 2.01 (1H), 2.10 to 2.61 (11H), 2.67 (1H), 4.30 (2H), 4.37 (1H), 5.73 (1H), 7.02-7.29 (9H) ppm.

Example 34a
1- [4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ′, 5 ′, 13-trimethyl-1,2,3,4, 6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) benzyl] -3- (4-chlorophenyl) urea

  Analogously to Example 32a, 40 mg (67 μmol) of the compound prepared according to Example 17b was converted with 4-chlorophenyl isocyanate to isolate 51 mg of the title compound as a crude product after work-up. .

Example 35
1- (4-t-Butylphenyl) -3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3 , 6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea

  Conversion of 51 mg (66 μmol) of the compound prepared according to Example 35a in the same manner as Example 1 gave 20.5 mg (46%) of the title compound as a colorless foam after work-up and purification.

  1H NMR (CDCl3): δ = 0.56 (3H), 1.28 (9H), 1.37-1.55 (2H), 1.71-1.87 (3H), 2.05 (1H), 2.15-2.62 (9H), 2.65 (1H), 2.69 (1H), 4.33 (2H), 4.40 (1H), 5.37 (1H), 5.76 (1H), 6.64 (1H), 7.09 (2H), 7.13 to 7.21 (4H), 7.30 (2H) ppm.

Example 35a
1- [4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ′, 5 ′, 13-trimethyl-1,2,3,4, 6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) benzyl] -3- (4-t-butylphenyl) urea

  Analogously to Example 32a, 40 mg (67 μmol) of the compound prepared according to Example 17b was converted with 4-t-butyl isocyanate to give 52 mg of the title compound as a crude product after work-up. It was done.

Example 36
4- {3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11 , 12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] ureido} benzoic acid ethyl ester

  Conversion of 67 mg (85 μmol) of the compound prepared according to Example 36a in the same way as Example 1 gave 21 mg of the title compound as a colorless foam (37%) after work-up and purification.

  1H NMR (CDCl3): δ = 0.58 (3H), 1.36 (3H), 1.39 to 1.54 (2H), 1.71 to 1.87 (3H), 1.98 to 2.22 (3H), 2.27 to 2.70 (8H), 3.25 (1H) 4.27 to 4.42 (5H), 5.75 (1H), 6.08 (1H), 7.08 (2H), 7.15 (2H), 7.36 (2H), 7.84 (2H), 7.90 (1H) ppm.

Example 36a
{3- [4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ', 5', 13-trimethyl-1,2,3,4 , 6,7,8,11,12,13,14,15,16,17-Tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) benzyl ] Ureido} -4-benzoic acid ethyl ester

  Analogously to Example 32a, 100 mg (0.17 mmol) of the compound prepared according to Example 17b was converted with ethyl 4-isocyanatobenzoate, which gave 137 mg of the title compound as a crude product after work-up. .

Example 37
1- [4- (3,5-Dimethylisoxazol-4-yl) phenyl] -3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3- Oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea

  Converting 49 mg (66 μmol) of the compound prepared according to Example 37a as in Example 1 yielded 9.1 mg (22%) of the title compound as a colorless foam after work-up and purification.

  1H NMR (CDCl3): δ = 0.52 (3H), 1.34 to 1.53 (2H), 1.68 to 1.83 (3H), 1.98 to 2.13 (4H), 2.10 (3H), 2.22 to 2.62 (9H), 2.27 (3H) 2.69 (1H), 4.30 (2H), 4.39 (1H), 5.75 (1H), 7.05 to 7.16 (4H) ppm.

Example 37a
1- [4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ′, 5 ′, 13-trimethyl-1,2,3,4, 6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) benzyl] -3- (3,5-dimethylisoxazolyl-4-yl) urea

  Analogously to Example 32a, 40 mg (67 μmol) of the compound prepared according to Example 17b was converted with 3,5-dimethylisoxazol-4-yl isocyanate to give the title compound after work-up. Was isolated as a crude product.

Example 38
4- {3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11 , 12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] ureido} benzoic acid

  Converting 71 mg (93 μmol) of the compound prepared according to Example 38a as in Example 1, converted 15 mg of the title compound as a colorless foam (26%) after work-up and purification.

  1H NMR (CD3OD): δ = 0.57 (3H), 1.25 to 1.56 (2H), 1.68 to 1.83 (3H), 2.02 to 2.46 (6H), 2.53 to 2.72 (4H), 2.79 (1H), 4.34 (2H) 4.50 (1H), 5.72 (1H), 7.20 (2H), 7.25 (2H), 7.41 (2H), 7.87 (2H) ppm.

Example 38a
{3- [4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ', 5', 13-trimethyl-1,2,3,4 , 6,7,8,11,12,13,14,15,16,17-Tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) benzyl ] Ureido} -4-benzoic acid

  Analogously to Example 26a, 69 mg (87 micromoles) of the compound prepared according to Example 36a were converted to isolate 71 mg of the title compound as a crude product after work-up.

Example 39
1- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] -3- (4-piperidin-1-ylphenyl) urea

  Conversion of 27 mg (34 μmol) of the compound prepared according to Example 39a in the same way as Example 1 gave 9.8 mg (42%) of the title compound as a colorless foam after work-up and purification.

  1H NMR (CDCl3): δ = 0.55 (3H), 1.37 to 1.86 (11H), 2.04 (1H), 2.16 to 2.62 (9H), 2.70 (1H), 2.79 (1H), 3.10 (4H), 4.33 (2H) ), 4.40 (1H), 5.15 (1H), 5.76 (1H), 6.37 (1H), 6.86 (2H), 7.05-7.17 (6H) ppm.

Example 39a
1- [4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ′, 5 ′, 13-trimethyl-1,2,3,4, 6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) benzyl] -3- (4-Piperidin-1-ylphenyl) urea

  Analogously to Example 32a, 40 mg (67 μmol) of the compound prepared according to Example 17b was converted with 4-piperidinylphenyl isocyanate to give 55 mg of the title compound as a crude product after work-up. Isolated.

Example 40
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-11- [4- (3-methyloxetane-3-yl) phenyl] -17-pentafluoroethyl-1,2,6, 7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one

  Converting 59 mg (92 μmol) of the compound prepared according to Example 40a as in Example 1, converted 24 mg of the title compound as a colorless foam (48%) after work-up and purification.

  1H NMR (CDCl3): δ = 0.60 (3H), 1.40 to 1.56 (2H), 1.70 (3H), 1.73 to 1.87 (3H), 2.06 (1H), 2.23 to 2.63 (10H), 2.75 (1H), 4.44 (1H), 4.63 (2H), 4.91 (2H), 5.78 (1H), 7.15 (4H) ppm.

Example 40a
(5R, 8S, 11R, 13S, 14S, 17S) -11- [4- (3-Methyloxetan-3-yl) phenyl] -5 ', 5', 13-trimethyl-17-pentafluoroethyl-1, 2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane]- 5,17-diol

  1 ml of a 2 molar solution of isopropylmagnesium chloride in tetrahydrofuran was mixed with 1.64 ml of a 2.5 molar solution of n-butyllithium in hexane at 5-10 ° C., and the mixture was stirred at 3 ° C. for 0.5 hours. A solution of 232 mg of 3- (4-bromophenyl) -3-methyloxetane in 1 ml of tetrahydrofuran was added dropwise and the resulting mixture was stirred at 3 ° C. for 2 hours. This mixture is then mixed with 3 mg of copper (I) chloride, and after 5 minutes 100 mg (0.2 mmol) of (5R, 8S, 10R, 13S, 14S, 17S) prepared as described in DE 102006054535. ) -17- (pentafluoroethyl) -5,10-epoxy-5 ', 5', 13-trimethyl-1,2,3,4,6,7,8,12,13,14,15,16, 17-Tridecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -17-ol was mixed with 1 ml of tetrahydrofuran and the resulting mixture was allowed to stand for 1.5%. Warmed to 23 ° C within hours. It was diluted with ethyl acetate, poured into saturated ammonium chloride solution and mixed with 25% ammonia solution. This mixture was extracted repeatedly with ethyl acetate and the combined organic extracts were washed with saturated sodium chloride solution and dried over sodium sulfate. The residue obtained after filtration and solvent removal was purified by chromatography. 59 mg of the title compound was isolated as a colorless foam (45%).

Example 41
Ethylcarbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester

  The crude product prepared according to Example 41a was converted in the same manner as in Example 1, and after work-up and purification, 19 mg of the title compound was isolated as a colorless foam (50%).

  1H NMR (CDCl3): δ = 0.60 (3H), 1.13 (3H), 1.39 to 1.57 (2H), 1.73 to 1.87 (3H), 2.06 (1H), 2.19 to 2.64 (10H), 2.72 (1H), 3.23 (2H), 4.44 (1H), 4.71 (1H), 5.03 (2H), 5.78 (1H), 7.16 (2H), 7.25 (2H) ppm.

Example 41a
Ethylcarbamic acid 4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ', 5', 13-trimethyl-1,2,3,4, 6,7,8,11,12,13,14,15,16,17-Tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) benzyl ester

  Analogously to Example 32a, 40 mg (67 micromol) of the compound prepared according to Example 17b was converted with ethyl isocyanate and the title compound obtained after workup was further converted as a crude product.

Example 42
Isopropylcarbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester

  The crude product prepared according to Example 42a was converted in the same manner as in Example 1, and after work-up and purification, 22.3 mg of the title compound was isolated as a colorless foam (58%).

  1H NMR (CDCl3): δ = 0.60 (3H), 1.15 (6H), 1.38 to 1.56 (2H), 1.72 to 1.87 (3H), 2.06 (1H), 2.20 to 2.65 (10H), 2.72 (1H), 3.82 (1H), 4.44 (1H), 4.58 (1H), 5.01 (2H), 5.78 (1H), 7.16 (2H), 7.25 (2H) ppm.

Example 42a
Isopropylcarbamic acid 4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ′, 5 ′, 13-trimethyl-1,2,3,4, 6,7,8,11,12,13,14,15,16,17-Tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) benzyl ester

  Analogously to Example 32a, 40 mg (67 micromol) of the compound prepared according to Example 17d was converted using isopropyl isocyanate, and the title compound obtained after workup was further converted as a crude product.

Example 43
Allylcarbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester

  Conversion of the crude product prepared according to Example 43a as in Example 1 gave 25 mg (63%) of the title compound as a colorless foam after work-up and purification.

  1H NMR (CDCl3): δ = 0.60 (3H), 1.38 to 1.56 (2H), 1.72 to 1.88 (3H), 2.06 (1H), 2.19 to 2.64 (10H), 2.72 (1H), 3.81 (1H), 4.44 (1H), 4.83 (1H), 5.05 (2H), 5.12 (1H), 5.18 (1H), 5.78 (1H), 5.83 (1H), 7.16 (2H), 7.26 (2H) ppm.

Example 43a
Allylcarbamic acid 4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ', 5', 13-trimethyl-1,2,3,4, 6,7,8,11,12,13,14,15,16,17-Tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) benzyl ester

  Analogously to Example 32a, 40 mg (67 μmol) of the compound prepared according to Example 17d was converted using allyl isocyanate, and the title compound obtained after workup was further converted as a crude product.

Example 44
t-Butylcarbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11, 12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester

  Conversion of the crude product prepared according to Example 44a as in Example 1 gave 15 mg of the title compound as a colorless foam (38%) after work-up and purification.

  1H NMR (CDCl3): δ = 0.59 (3H), 1.32 (9H), 1.40 to 1.56 (2H), 1.73 to 1.87 (3H), 2.06 (1H), 2.20 to 2.64 (10H), 2.72 (1H), 4.44 (1H), 4.71 (1H), 4.99 (2H), 5.78 (1H), 7.16 (2H), 7.25 (2H) ppm.

Example 44a
t-Butylcarbamic acid 4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ', 5', 13-trimethyl-1,2,3, 4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) Benzyl ester

  Analogously to Example 32a, 40 mg (67 μmol) of the compound prepared according to Example 17d are converted with t-butyl isocyanate and the title compound obtained after work-up is further converted as a crude product. did.

Example 45
(4-Piperidin-1-ylphenyl) carbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6 , 7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester

  Conversion of the crude product prepared according to Example 45a as in Example 1 gave 7.8 mg (17%) of the title compound as a colorless foam after work-up and purification.

  1H NMR (CDCl3): δ = 0.59 (3H), 1.41-1.59 (4H), 1.65-1.85 (7H), 2.06 (1H), 2.12 (1H), 2.22-2.63 (9H), 2.72 (1H), 3.08 (4H), 4.45 (1H), 5.14 (2H), 5.78 (1H), 6.52 (1H), 6.89 (2H), 7.17 (2H), 7.24 (2H), 7.31 (2H) ppm.

Example 45a
(4-Piperidin-1-ylphenyl) carbamic acid 4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ', 5', 13-trimethyl -1,2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] Dioxane] -11-yl) benzyl ester

  Analogously to Example 32a, 40 mg (67 μmol) of the compound prepared according to Example 17d was converted with 4-piperidinylphenyl isocyanate and the title compound obtained after workup was converted to the crude product As further converted.

Example 46
Phenylcarbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester

  Conversion of the crude product prepared according to Example 46a as in Example 1 gave 13 mg (34%) of the title compound as a colorless foam after work-up and purification.

  1H NMR (CDCl3): δ = 0.60 (3H), 1.38 to 1.56 (2H), 1.73 to 1.87 (3H), 2.06 (1H), 2.10 (1H), 2.20 to 2.64 (9H), 2.72 (1H), 4.45 (1H), 5.16 (2H), 5.79 (1H), 6.67 (1H), 7.07 (1H), 7.18 (2H), 7.25-7.40 (6H) ppm.

Example 46a
Phenylcarbamic acid 4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ', 5', 13-trimethyl-1,2,3,4, 6,7,8,11,12,13,14,15,16,17-Tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) benzyl ester

  Analogously to Example 32a, 40 mg (67 μmol) of the compound prepared according to Example 17d was converted with phenyl isocyanate and the title compound obtained after workup was further converted as a crude product.

Example 47
(4-Methoxyphenyl) carbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8 , 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester

  Conversion of the crude product prepared according to Example 47a as in Example 1 yielded 4.5 mg of the title compound as a colorless foam (10%) after work-up and purification.

  1H NMR (CDCl3): δ = 0.60 (3H), 1.40 to 1.55 (2H), 1.73 to 1.87 (3H), 2.02 (1H), 2.06 (1H), 2.21 to 2.64 (9H), 2.72 (1H), 3.78 (3H), 4.45 (1H), 5.15 (2H), 5.78 (1H), 6.53 (1H), 6.85 (2H), 7.18 (2H), 7.28-7.34 (4H) ppm.

Example 47a
(4-Methoxyphenyl) carbamic acid 4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ', 5', 13-trimethyl-1,2 , 3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11 -Il) benzyl ester

  Analogously to Example 32a, 40 mg (67 μmol) of the compound prepared according to Example 17d were converted using 4-methoxyphenyl isocyanate, and the title compound obtained after work-up was further purified as a crude product. Converted.

Example 48
(4-Methylphenyl) carbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8 , 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester

  Conversion of the crude product prepared according to Example 48a as in Example 1 gave 5.9 mg (14%) of the title compound as a colorless foam after work-up and purification.

1H NMR (CDCl3): δ = 0.60 (3H), 1.39 to 1.55 (2H), 1.73 to 1.87 (3H), 2.04 (1H), 2.07 (1H), 2.20 to 2.64 (9H), 2.30 (3H), 2.72 (1H), 4.45 (1H), 5.15 (2H), 5.78 (1H), 6.58 (1H), 7.10 (2H), 7.18 (2H), 7.25 (2H), 7.32 (2H) ppm.

Example 48a
(4-Methylphenyl) carbamic acid 4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ', 5', 13-trimethyl-1,2 , 3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11 -Il) benzyl ester

  Analogously to Example 32a, 40 mg (67 μmol) of the compound prepared according to Example 17d was converted using 4-tolyl isocyanate, and the title compound obtained after workup was further converted as a crude product. did.

Example 49
(4-Fluorophenyl) carbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8 , 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester

  Conversion of the crude product prepared according to Example 49a as in Example 1 gave 6 mg (14%) of the title compound as a colorless foam after work-up and purification.

  1H NMR (CDCl3): δ = 0.60 (3H), 1.39 to 1.56 (2H), 1.73 to 1.87 (3H), 2.05 (1H), 2.07 (1H), 2.20 to 2.65 (9H), 2.72 (1H), 4.45 (1H), 5.15 (2H), 5.79 (1H), 6.63 (1H), 7.00 (2H), 7.18 (2H), 7.28-7.34 (4H) ppm.

Example 49a
(4-Fluorophenyl) carbamic acid 4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ', 5', 13-trimethyl-1,2 , 3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11 -Il) benzyl ester

  Analogously to Example 32a, 40 mg (67 μmol) of the compound prepared according to Example 17d was converted with 4-fluorophenyl isocyanate, and the title compound obtained after work-up was further treated as a crude product. Converted.

Example 50
(4-Chlorophenyl) carbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8, 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester

  Conversion of the crude product prepared according to Example 50a as in Example 1 yielded 8.5 mg of the title compound as a colorless foam (20%) after work-up and purification.

  1H NMR (CDCl3): δ = 0.60 (3H), 1.39 to 1.56 (2H), 1.73 to 1.87 (3H), 2.06 (1H), 2.07 (1H), 2.19 to 2.64 (9H), 2.72 (1H), 4.46 (1H), 5.15 (2H), 5.78 (1H), 6.68 (1H), 7.19 (2H), 7.22-7.36 (6H) ppm.

Example 50a
(4-Chlorophenyl) carbamic acid 4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ', 5', 13-trimethyl-1,2, 3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11- Yl) benzyl ester

  Analogously to Example 32a, 40 mg (67 μmol) of the compound prepared according to Example 17d was converted with 4-chlorophenyl isocyanate and the title compound obtained after workup was further converted as a crude product. did.

Example 51
(4-t-Butylphenyl) carbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7 , 8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester

  Conversion of the crude product prepared according to Example 51a as in Example 1 gave 5.2 mg of the title compound as a colorless foam (12%) after work-up and purification.

  1H NMR (CDCl3): δ = 0.60 (3H), 1.30 (9H), 1.40 to 1.55 (2H), 1.73 to 1.87 (3H), 2.02 (1H), 2.06 (1H), 2.21 to 2.64 (9H), 2.73 (1H), 4.45 (1H), 5.16 (2H), 5.79 (1H), 6.60 (1H), 6.65 (2H), 7.19 (2H), 7.28-7.34 (4H) ppm.

Example 51a
(4-t-Butylphenyl) carbamic acid 4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ', 5', 13-trimethyl-1 , 2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) benzyl ester

  Analogously to Example 32a, 40 mg (67 μmol) of the compound prepared according to Example 17d were converted with t-butylphenyl isocyanate and the title compound obtained after work-up was further purified as a crude product. Converted.

Example 52
4- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyloxycarbonylamino] benzoic acid ethyl ester

  Conversion of the crude product prepared according to Example 52a as in Example 1 gave 10 mg (24%) of the title compound as a colorless foam after work-up and purification.

  1H NMR (CDCl3): δ = 0.60 (3H), 1.38 (3H), 1.38 to 1.55 (2H), 1.74 to 1.87 (3H), 2.02 (1H), 2.06 (1H), 2.20 to 2.64 (9H), 2.73 (1H), 4.35 (2H), 4.46 (1H), 5.18 (2H), 5.78 (1H), 6.85 (1H), 7.19 (2H), 7.32 (2H), 7.45 (2H), 7.99 (2H) ppm.

Example 52a
4- [4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ', 5', 13-trimethyl-1,2,3,4, 6,7,8,11,12,13,14,15,16,17-Tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) benzyloxy Carbonylamino] benzoic acid ethyl ester

  Analogously to Example 32a, 40 mg (67 μmol) of the compound prepared according to Example 17d were converted with ethyl 4-isocyanatobenzoate and the title compound obtained after work-up was further purified as a crude product. Converted.

Example 53
[4- (3,5-Dimethylisoxazol-4-yl) phenyl] carbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17- Pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester

  Conversion of the crude product prepared according to Example 53a as in Example 1 gave 8.6 mg (20%) of the title compound as a colorless foam after work-up and purification.

  1H NMR (CDCl3): δ = 0.59 (3H), 1.39 to 1.57 (2H), 1.72 to 1.88 (3H), 1.99 to 2.65 (17H), 2.73 (1H), 4.45 (1H), 5.13 (2H), 5.79 (1H), 5.86 (1H), 7.19 (2H), 7.28 (2H) ppm.

Example 53a
[4- (3,5-Dimethylisoxazol-4-yl) phenyl] carbamic acid 4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl- 5 ', 5', 13-trimethyl-1,2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3 , 2 '-[1,3] Dioxane] -11-yl) benzyl ester

  In the same way as Example 32a, 40 mg (67 micromol) of the compound prepared according to Example 17d was converted with 3,5-dimethylisoxazol-4-yl isocyanate and the title obtained after work-up This compound was further converted as a crude product.

Example 54
N- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] nicotinamide

  Converting 48 mg (68 μmol) of the compound prepared according to Example 54a as in Example 1 yielded 5.0 mg of the title compound as a colorless foam (13%) after work-up and purification.

  1H NMR (CDCl3): δ = 0.60 (3H), 1.38 to 1.56 (2H), 1.72 to 1.88 (3H), 2.06 (1H), 2.18 to 2.63 (9H), 2.66 (1H), 2.72 (1H), 4.43 (1H), 4.61 (2H), 5.77 (1H), 6.63 (1H), 7.15 (2H), 7.25 (2H), 7.39 (1H), 8.14 (1H), 8.71 (1H), 8.96 (1H) ppm.

Example 54a
N- [4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ′, 5 ′, 13-trimethyl-1,2,3,4, 6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) benzyl] Nicotinamide

  A solution of 40 mg (67 μmol) of the compound prepared according to Example 17b in 1 ml dichloromethane and 20 μl dimethylformamide was mixed with 9 mg nicotinyl chloride and stirred at 23 ° C. for 2 hours. The mixture was concentrated and the resulting compositional organism was further converted without purification.

Example 55
3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyloxycarbonylamino] propionic acid

  Conversion of 52 mg (73 μmol) of the compound prepared according to Example 55a as in Example 1 gave 14 mg of the title compound as a colorless foam (32%) after work-up and purification.

  1H NMR (CD3OD): δ = 0.57 (3H), 1.36 to 1.56 (2H), 1.70 to 1.82 (3H), 2.09 (1H), 2.16 to 2.46 (7H), 2.54 to 2.73 (4H), 2.79 (1H) 3.33 (2H), 4.52 (1H), 5.00 (2H), 5.73 (1H), 7.21 (2H), 7.26 (2H) ppm.

Example 55a
3- [4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ', 5', 13-trimethyl-1,2,3,4, 6,7,8,11,12,13,14,15,16,17-Tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) benzyloxy Carbonylamino] propionic acid

  Converting 82 mg (0.11 mmol) of the compound prepared according to Example 55b in the same way as Example 26a converted 59 mg of the title compound as a colorless foam (77%) after work-up.

Example 55b
3- [4-((5R, 8S, 11R, 13S, 14S, 17S) -5,17-dihydroxy-17-pentafluoroethyl-5 ', 5', 13-trimethyl-1,2,3,4, 6,7,8,11,12,13,14,15,16,17-Tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '-[1,3] dioxane] -11-yl) benzyloxy Carbonylamino] propionic acid ethyl ester

  Analogously to Example 32a, 100 mg (0.17 mmol) of the compound prepared according to Example 17d was converted with ethyl 3-isocyanatopropionate and the title compound obtained after work-up was further purified as a crude product. Converted.

Example 56
Benzylcarbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester

  Analogously to Example 32a, 50 mg (83 μmol) of the compound prepared according to Example 17d was converted using benzyl isocyanate, and the title compound obtained after work-up was further treated as in Example 1. Converted. After work-up and purification, 14 mg of the title compound was isolated as a colorless foam (27%).

  1H NMR (CDCl3): δ = 0.59 (3H), 1.42-1.55 (2H), 1.75-1.86 (3H), 2.06 (1H), 2.22-2.63 (10H), 2.72 (1H), 4.39 (2H), 4.45 (1H), 5.05 (1H), 5.09 (2H), 5.78 (1H), 7.17 (2H), 7.24-7.35 (7H) ppm.

Example 57
3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyloxycarbonylamino] propionic acid ethyl ester

  Converting 72 mg (97 μmol) of the compound prepared according to Example 55b in the same way as Example 1 yielded 6.1 mg of the title compound as a colorless foam (10%) after work-up and purification.

  1H NMR (CDCl3): δ = 0.59 (3H), 1.26 (3H), 1.42-1.56 (2H), 1.74-1.89 (3H), 2.07 (1H), 2.14 (1H), 2.22-2.67 (11H), 2.72 (1H), 3.47 (2H), 4.14 (2H), 4.45 (1H), 5.04 (1H), 5.28 (1H), 5.78 (1H), 7.16 (2H), 7.26 (2H) ppm.

Example 58
Progesterone receptor antagonism in human neuroblastoma cells (SK-N-MC cells) stably transfected with human progesterone receptor A or progesterone receptor B and MTV-LUC reporter construct

Express reporter constructs with plasmids expressing human progesterone receptor B (pRChPR-B-neo) or human progesterone receptor A (pRChPR-A-neo) to determine the agonist effect rate SK-N-MC cells (human neuroblastoma cells) stably transfected with the plasmid (pMMTV-LUC) were added in increasing amounts of each test compound (0.01 nmol / liter, 0.1 nmol / liter, Incubated for 24 hours in the presence of 1 nanomole / liter, 10 nanomole / liter, 100 nanomole / liter, 1 micromole / liter) or in the absence (negative control). As a positive control to induce the reporter gene, cells are synthesized with the synthetic gestagen promegestone (0.01 nmol / liter, 0.1 nmol / liter, 1 nmol / liter, 10 nmol / liter, 100 nmol / liter, 1 micromol / liter) Processed. To determine antagonistic activity, cells are treated with 0.1 nmol / liter promegestone, plus increasing amounts of each test compound (0.01 nmol / liter, 0.1 nmol / liter, 1 nmol / liter, 10 nmol / liter). Liter, 100 nanomole / liter, 1 micromole / liter). The activity of the LUC reporter gene (LUC = luciferase) was determined in the cell lysate and measured as RLU (relative light units). All measurements are given as percent effect and EC ₅₀ and IC ₅₀ concentrations.

  a) Agonist activity:

  None of the above test compounds showed agonist activity.

  b) Antagonistic activity:

  All the above test compounds show 100% antagonistic activity.

The antagonistic effects of the compounds are shown in Table 1.

Compounds having an antagonistic effect with an IC ₅₀ of less than 1.0 nM are preferred.

Compounds having an antagonistic effect with an IC ₅₀ of 0.1 nM or less are particularly preferred.

Example 59
Measurement of metabolic stability in human and rat liver microsomes.

  The metabolic stability of the compound of general formula (I) was evaluated using the isolated human liver microsome (HLM).

  2.4 ml HLM solution (containing 0.5 mg / ml protein), 30 μl test compound (final concentration 1 μM), 0.6 ml cofactor mixture (= 3 IU glucose-6-phosphate dehydrogenase, 14.6 mg glucose Incubation was performed using NADPH production system consisting of -6-phosphate and 1.2 mg NADP at 37 ° C. in 100 mM phosphate buffer (pH 7.4). Samples were taken at 6 time points (2-60 minutes), precipitated with the same volume of methanol and examined by LC-MS / MS analysis to see how much of the test substance used was recovered in the supernatant . Using the half-life determined from the analysis for the degradation of the substance, the so-called intrinsic clearance of the substance contained in the liver microsome preparation was calculated. And based on various physiological parameters (human liver blood flow: 1.3 liter kg / hr; liver specific gravity (per kg body weight): 21 g / kg; microsomal protein content: 40 mg per g liver) according to well-stirred models Predicted (metabolic) in vivo clearance for stage I reactions. In addition, maximal oral bioavailability (Fmax) is assumed, assuming (i) 100% absorption of the test substance and (ii) first pass is fully reflected in liver microsomal metabolism. Calculated.

  Some of the compounds tested are particularly suitable for topical administration that requires low systemic stability because the expected oral bioavailability Fmax in humans is less than 50%. Examples include the compounds of Examples 2-9, 15, 17, 23, 24, 40, 41 (see Table 2).

  Highly preferred for systemic administration is more than 60% of each compound in species (rat, human) with different expected maximum bioavailability.

  Highly preferred for topical administration are compounds with a maximum bioavailability expected in humans of less than 50%.

Claims (15)

Compounds of general formula (I):

(Where
R ¹ is defined as an R ^1a group bonded to the phenyl ring at the m-position or p-position, or is defined as an R ^1b group bonded to the phenyl ring only at the m-position,
R ^1a is (CH ₂ ) nR ² , C (R ³ ) 2OH, CN, C (CH ₂ OH) 2R ³ , C (CH ₂ OCH ₂ ) R ³ ,

Selected from the group containing
R ^1b is selected from the group comprising C ₂ -C ₁₀ -acyl, CHOH alkyl;
R ² is aryl, heteroaryl, are selected from halogen, CN, N _3, OH, from the group including ^{NHCONHR 4, OCONHR 4, NHCOR 4} ,
R ³ is selected from the group comprising hydrogen, C ₁ -C ₁₀ -alkyl,
R ⁴ is hydrogen, C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl, C ₇ -C ₂₀ -aralkyl, aryl, heteroaryl, (CH ₂ ) _q CO ₂ R ⁵ ,

Selected from the group containing
n is 1 or 2,
q is 1 to 10,
R ⁵ is selected from the group comprising hydrogen, C ₁ -C ₁₀ -alkyl, CH ₂ OH,
X is selected from the group comprising oxygen, NOR ⁶ , NNHSO ₂ R ⁶
Y is selected from the group comprising oxygen, CHR ⁶ , NR ⁶
R ⁶ is selected from the group comprising hydrogen, C ₁ -C ₁₀ -alkyl, aryl, C ₇ -C ₂₀ -aralkyl) and salts of the compounds, solvates of the compounds, Solvates, including all the crystalline polymorphs, α-, β-, γ-cyclodextrin acrylate, and the above compounds encapsulated with liposomes. Compound of general formula (II) in claim 1:

(Where
A is -O- or -NH-
R ⁷ is C ₁ -C ₄ -alkyl, allyl, where the para position is optionally C ₁ -C ₄ -alkyl, -CN, C ₁ -C ₄ -alkoxy, halogen, C ₁ -C ₄ -alkanoyloxy, _{- CO 2 H, - CO 2} C 1 ~ 4 - alkyl, phenyl substituted with one of piperidinyl,

,
Benzyl, — (CH ₂ ) m —COOR ⁸ (where m = 1, 2, 3 and R ⁸ = hydrogen or C ₁ -C ₄ -alkyl) and a salt of the compound, Solvates of compounds, solvates of the salts, including any of the crystalline polymorphs, the compounds encapsulated using α-, β-, γ-cyclodextrin acrylate, liposomes. Compound of general formula (III) in claim 2:

(Where
A is -O- or -NH-
R ⁹ is hydrogen, C ₁ -C ₄ - alkyl, -CN, C ₁ ~C ₄ - alkoxy, halogen, C ₁ -C ₄ - _{alkanoyloxy, - CO 2 H, - CO} 2 C 1 ~ 4 - alkyl , Piperidyl), a salt of the compound, a solvate of the compound, a solvate of the salt, including any crystalline polymorph, α-, β-, γ-cyclodextrin Clatrate, and the above compounds encapsulated using liposomes are included). Compound of general formula (IV) in claim 1:

(Where
R ¹⁰ is pyridinyl or thiazoyl optionally substituted with methyl, or —CN, —OH, and a salt of the compound, a solvate of the compound, a solvate of the salt (of which Includes any of the crystalline polymorphs, α-, β-, γ-cyclodextrin acrylate, and the aforementioned compounds encapsulated using liposomes). Compound of general formula (V) in claim 1:

(Where
R ¹¹ is either C ₁ -C ₄ -alkyl optionally substituted with hydroxyl, C ₁ -C ₄ -alkanoyloxy, optionally cyclopropyl optionally substituted with methyl) and of the compound Salts, solvates of the compounds, solvates of the salts, including any of the crystalline polymorphs, α-, β-, γ-cyclodextrin acrylate, and the compounds encapsulated using liposomes ) Among the compounds according to claim 1,
(8S, 11a3S, 14S, 17S) -11- (4-Cyclopropylphenyl) -17-hydroxy-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13, 14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 1),
(8S, 11R, 13S, 14S, 17S) -17-Hydroxy-13-methyl-17-pentafluoroethyl-11- [4- (2-pyridin-2-ylethyl) phenyl] -1,2,6,7 , 8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 2),
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-11- {4- [2- (2-methylthiazol-4-yl) ethyl] phenyl} -17-pentafluoroethyl-1, 2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 3),
(8S, 11R, 13S, 14S, 17S) -17-Hydroxy-13-methyl-11- [4- (1-methylcyclopropyl) phenyl] -17-pentafluoroethyl-1,2,6,7,8 , 11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 4),
(8S, 11R, 13S, 14S, 17S) -17-Hydroxy-11- [4- (1-hydroxy-1-methylethyl) phenyl] -13-methyl-17-pentafluoroethyl-1,2,6, 7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 5),
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-11- [4-((1R, 2R or 1S, 2S) -2-hydroxymethylcyclopropyl) phenyl-13-methyl-17-pentafluoroethyl -1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 6),
(8S, 11R, 13S, 14S, 17S) -17-Hydroxy-13-methyl-17-pentafluoroethyl-11- [4- (2-pyridin-3-ylethyl) phenyl] -1,2,6,7 , 8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 7),
(8S, 11R, 13S, 14S, 17S) -17-Hydroxy-13-methyl-17-pentafluoroethyl-11- [4- (2-pyridin-4-ylethyl) phenyl] -1,2,6,7 , 8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 8),
3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) phenyl] propionitrile (Example 9),
(8S, 11R, 13S, 14S, 17S) -11- (3-Acetylphenyl) -17-hydroxy-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13 , 14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 10),
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-11- [3-((RS) -1-hydroxyethyl] phenyl] -13-methyl-17-pentafluoroethyl-1,2,6, 7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 11),
(8S, 11R, 13S, 14S, 17S) -11- (3-Cyclopropylphenyl) -17-hydroxy-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12, 13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 12),
(8S, 11R, 13S, 14S, 17S) -17-Hydroxy-13-methyl-11- [3- (1-methylcyclopropyl) phenyl] -17-pentafluoroethyl-1,2,6,7,8 , 11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 13),
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-11- [3- (2-hydroxyethyl) phenyl] -13-methyl-17-pentafluoroethyl-1,2,6,7,8, 11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 14),
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-11- [4- (2-hydroxy-1-hydroxymethyl-1-methylethyl) phenyl] -13-methyl-17-pentafluoroethyl-1 , 2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 15),
(8S, 11R, 13S, 14S, 17S) -17-Hydroxy-13-methyl-17-pentafluoroethyl-11- [4- (2,2,5-trimethyl- [1,3] dioxan-5-yl ) Phenyl] -1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 15),
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-11- [4- (2-hydroxy-1-hydroxymethylethyl) phenyl] -13-methyl-17-pentafluoroethyl-1,2,6 , 7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 16),
1-ethyl-3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8, 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea (Example 17),
1-allyl-3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8, 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea (Example 18),
1-isopropyl-3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8, 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea (Example 19),
1-t-butyl-3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7, 8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea (Example 20),
{3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12 , 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] ureido} acetic acid ethyl ester (Example 21),
3- {3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11 , 12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] ureido} propionic acid ethyl ester (Example 22),
1-benzyl-3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8, 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea (Example 23),
1-phenyl-3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8, 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea (Example 24),
1- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] -3-p-tolylurea (Example 25),
{3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12 , 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] ureido} acetic acid (Example 26),
3- {3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11 , 12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] ureido} propionic acid (Example 27),
(8S, 11R, 13S, 14S, 17S) -11- (4-Azidomethylphenyl) -17-hydroxy-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12, 13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 28),
(8S, 11R, 13S, 14S, 17S) -17-Hydroxy-13-methyl-17-pentafluoroethyl-11- [4 '-(1H-tetrazol-5-yl) biphenyl-4-yl] -1, 2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 29),
4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14 , 15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzonitrile (Example 30),
(8S, 11R, 13S, 14S, 17S) -17-Hydroxy-13-methyl-17-pentafluoroethyl-11- [4- (1H-tetrazol-5-yl) phenyl] -1,2,6,7 , 8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 31),
1- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] -3- (4-methoxyphenyl) urea (Example 32),
1- (4-Fluorophenyl) -3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6 , 7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea (Example 33),
1- (4-chlorophenyl) -3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6, 7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea (Example 34),
1- (4-t-Butylphenyl) -3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3 , 6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea (Example 35),
4- {3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11 , 12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] ureido} benzoic acid ethyl ester (Example 36),
1- [4- (3,5-Dimethylisoxazol-4-yl) phenyl] -3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3- Oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] urea ( Example 37),
4- {3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11 , 12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] ureido} benzoic acid (Example 38),
1- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] -3- (4-piperidin-1-ylphenyl) urea (Example 39),
(8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-11- [4- (3-methyloxetane-3-yl) phenyl] -17-pentafluoroethyl-1,2,6, 7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta [a] phenanthren-3-one (Example 40),
Ethylcarbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 41),
Isopropylcarbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 42),
Allylcarbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 43),
t-Butylcarbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11, 12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 44),
(4-Piperidin-1-ylphenyl) carbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6 , 7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 45),
Phenylcarbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 46),
(4-Methoxyphenyl) carbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8 , 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 47),
(4-Methylphenyl) carbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8 , 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 48),
(4-Fluorophenyl) carbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8 , 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 49),
(4-Chlorophenyl) carbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8, 11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 50),
(4-t-Butylphenyl) carbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7 , 8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 51),
4- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyloxycarbonylamino] benzoic acid ethyl ester (Example 52),
[4- (3,5-Dimethylisoxazol-4-yl) phenyl] carbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17- Pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 53),
N- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl] nicotinamide (Example 54),
3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyloxycarbonylamino] propionic acid (Example 55),
Benzylcarbamic acid 4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyl ester (Example 56),
3- [4-((8S, 11R, 13S, 14S, 17S) -17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12, 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthren-11-yl) benzyloxycarbonylamino] propionic acid ethyl ester (Example 57).   The compound according to any one of claims 1 to 6, which exhibits a progesterone receptor antagonism among stable transfectants of human fibroblastoma cells (see Example 58). Any one of claims 1 to 6, which exhibits an antagonistic effect with a progesterone receptor having an IC ₅₀ value of 1 nM or less among stable transfectants of human fibroblastoma cells in vitro (see Example 58). The compound according to claim 1.   9. A compound according to any one of claims 1 to 8 for the treatment and prevention of various diseases.   For treatment and / or prevention of uterine fibroids, endometriosis, severe menstrual bleeding, meningioma, hormone-dependent breast cancer, complaints associated with menopause, or for birth control and emergency contraception 9. The compound according to any one of 8.   Use of the compound according to any one of claims 1 to 8 for the manufacture of a medicament for the treatment and / or prevention of various diseases.   Manufactures drugs for the treatment and / or prevention of uterine fibroids, endometriosis, severe menstrual bleeding, meningiomas, hormone-dependent breast cancer, complaints associated with menopause, or birth control and emergency contraception Use of a compound according to any one of claims 1 to 8 for the purpose.   A medicament comprising the compound according to any one of claims 1 to 8 in combination with another active ingredient.   A medicament comprising the compound according to any one of claims 1 to 8 in combination with an inert non-toxic excipient suitable for a medicament.   Claim 13 or for the treatment and / or prevention of uterine fibroids, endometriosis, severe menstrual bleeding, meningiomas, hormone-dependent breast cancer, complaints associated with menopause, or for birth control and emergency contraception 14. The medicament according to 14.